Compounds Useful as Antagonists of CCR2

ABSTRACT

The present invention provides compounds of general formula (I) or a pharmaceutically acceptable salt thereof, wherein X, n, Y, and R 1  are defined generally and in subsets herein. Compounds of the invention are inhibitors of CCR2 and accordingly are useful for the treatment of a variety of inflammatory, allergic, and autoimmune diseases, disorders, or conditions.

BACKGROUND OF THE INVENTION

Chemoattractant cytokines, Chemoattractant cytokines or chemokines are afamily of proinflammatory mediators that are released by a wide varietyof cells to promote recruitment and activation of cells such as T and Blymphocytes, eosinophils, basophils, and neutrophils (Luster et al. NewEng. J. Med, 1998, 338, 436). The chemokines are related in primarystructure and contain four conserved cysteines, which form disulfidebonds. The chemokine family includes the C—X—C chemokines(α-chemokines), and the C—C chemokines (β-chemokines), in which thefirst two conserved cysteines are separated by an intervening residue,or are adjacent, respectively (Baggiolini, M. and Dahinden, C. A.,Immunology Today, 1994, 15, 127).

Chemokines exert their biological activity by binding to specificcell-surface receptors belonging to the family of G-protein-coupledseven-transmembrane-domain proteins (Horuk, Trends Pharm. Sci. 1994, 15,159) which are termed “chemokine receptors”. On binding their cognateligands, chemokine receptors then transduce signals important for thedevelopment and trafficking of specific leukocyte subsets (Baggiolini,et. al., Nature 1994, 15, 365). The chemokines and their cognatereceptors have been implicated as being important mediators ofinflammatory, and allergic diseases, disorders, and conditions, as wellas autoimmune pathologies such as rheumatoid arthritis andatherosclerosis (see, Carter, Current Opinion in Chemical Biology 2002,6, 510; Trivedi et al., Ann. Reports Med. Chem. 2000, 35, 191; Saunderset al., Drug Disc. Today 1999, 4, 80; and Premack et al., NatureMedicine, 1996, 2, 1174). Accordingly, agents that block the interactionof chemokines with their cognate receptors would be useful in treatinginflammatory, allergic, and autoimmune diseases, disorders, orconditions caused by aberrant activation of leukocytes or lymphocytes.

CCR2 is a chemokine receptor expressed on monocytes which recognizes theligands MCP-1, MCP-2, MCP-3, and MCP-4 (see, Berkhout, et al., J. Biol.Chem. 1997, 272, 16404. It has been implicated that the interaction ofmonocyte chemoattractant protein-1 (MCP-1) and its receptor (CCR2) playsa role in the pathogenesis of inflammatory, allergic, and autoimmunediseases (for example rheumatoid arthritis, multiple sclerosis, COPD,neuropathic pain, asthma, and atherosclerosis) by attracting leukocytesto sites of inflammation and subsequently activating these cells. Whenthe chemokine MCP-1 binds to CCR2, it induces a rapid increase inintracellular calcium concentration, increased expression of cellularadhesion molecules, cellular degranulation, and the promotion ofleukocyte migration. (see Dawson, et al., Expert Opin. Ther. Targets,2003, 7, 35; Gongh et al., J. Exp. Med. 1997, 181, 131; Izikson, et al.,Clin. Immunol. 2002, 103, 125; Donnelly et al., Drugs, 2003, 63, 1973;Leonard, E. J. Challenges Mod. Med., 1994, 3, 25; and Ross, R. New Engl.J. Med. 1999, 147, 213). In particular, monocyte chemoattractantprotein-1 (MCP-1) is believed to be primarily responsible for theselective recruitment of leukocytes to the site of inflammation bybinding to its receptor CCR2 on the surface of monocytes and macrophages(Rollins et al., Blood, 1997, 90, 909; Howard et al., Trends Biotechiol.1996, 14, 46; Saunders et al., Drug Discovery Today, 1999, 4, 80; Murphyet al., Pharmacologic Rev., 2000, 52, 145; and Horuk, R. Cytokine GrowthFactor Rev., 2001, 12, 313). The importance of the MCP-1/CCR2interaction has been demonstrated by experiments with geneticallymodified mice (see, Bao, et al., J. Exp. Med. 1998, 187, 601; Boring etal., J. Clin. Invest. 1997, 100, 2552; Kuziel et al., Proc. Natl. Acad.Sci. USA, 1997, 94, 12053; and Kurihara et al., J. Exp. Med. 1997, 186,1757). Several studies have also been published indicating thattherapeutic intervention at the CCR2 receptor via inhibition of theinteraction between MCP-1 and CCR2 may have beneficial effects in avariety of inflammatory, allergic, and autoimmune diseases. For example,studies completed to date have indicated that the antagonisum of theMCP-1/CCR2 interaction may be useful in treating rheumatoid arthritis;ameliorate chronic polyadjuvant-induced arthritis (Youssef et al., J.Clin. Invest. 2000, 106, 361); collagen-induced arthritis (Ogata et al.,J. Pathol. 1997, 182, 106); streptococcal cell wall-induced arthritis(Schimmer et al., J. Immunol. 1998, 160, 1466); MRL-1pr mouse model ofarthritis (Gong et al., J. Exp. Med. 1997, 186, 131); atherosclerosis(Rezaie-Majd et al, Arterioscler. Thromb. Vasc. Biol. 2002, 22,1194-1199; Gu et al., Mol. Cell. 1998, 2, 275; Gosling et al., J. Clin.Invest. 1999, 103, 773; Boring et al, Nature 1998, 394, 894; and Ni etal. Circulation 2001, 103, 2096-2101); multiple sclerosis (larlori etal., J. Neuroimmunol. 2002, 123, 170-179; Kennedy et al., J.Neuroimmunol. 1998, 92, 98; Fife et al., J. Exp. Med. 2000, 192, 899;and Izikson et al., J. Exp. Med. 2000, 192, 1075); organ transplantrejection (Reynaud-Gaubert et al., J. of Heart and Lung Transplant.,2002, 21, 721-730; Belperio et al., J. Clin. Invest. 2001, 108, 547-556;and Belperio et al., J. Clin. Invest. 2001, 108, 547-556); asthma(Gonzalo et al., J. Exp. Med. 1998, 188, 157; Lukacs, et al., J.Immunol. 1997, 158, 4398; and Lu et al., J. Exp. Med. 1998, 187, 601);kidney disease (Lloyd et al., J. Exp. Med. 1997, 185, 1371; and Tesch etal., J. Clin. Invest. 1999, 103, 73); lupus erythematosus (Tesch et al.,J. Exp. Med. 1999, 190, 1813); colitis (Andres et al., J. Immunol. 2000,164, 6303); alveolitis (Jones, et al., J. Immunol. 1992, 149, 2147);cancer (Conti, et al., Seminars in Cancer Biology 2004, 14, 149; Salcedoet al., Blood 2000, 96, 34-40); restinosis (Roque et al. Arterioscler.Thromb. Vasc. Biol. 2002, 22, 554-559); inflammatory bowel disease(Reinecker et al., Gastroenterology 1995, 108, 40; and Grimm et al., J.Leukoc. Biol. 1996, 59, 804); brain trauma (King et al., J.Neuroimmunol. 1994, 56, 127; and Berman et al., J. Immunol. 1996, 156,3017); transplant arteriosclerosis (Russell et al., Proc. Natl. Acad.Sci. USA 1993, 90, 6086); idiopathic pulmonary fibrosis (Antoniades etal., Proc. Natl. Acad. Sci. USA 1992, 89, 5371); psoriasis (Deleuran etal., J. Dennatol. Sci. 1996, 13, 228; and Gillitzer et al., J. Invest.Dernatol. 1993, 101, 127); HIV and HIV-1-associated dementia(Garzino-Demo, WO 99/46991; Doranz et al., Cell 1996, 85, 1149; Connoret al., J. Exp. Med. 1997, 185, 621; and Smith et al., Science 1997,277, 959); and neuropathic pain (Abbadie, et al., Proc. Natl. Acad. Sci.USA 2003, 100, 7947). Similarly, demonstration of the importance of theMCP-1/CCR-2 interaction has been reported in the literature. Forexample, Lu et al., J. Exp. Med. 1998, 187, 601; Boring et al., J. Clin.Invest. 1997, 100, 2552; Kuziel et al., Proc. Natl. Acad. Sci. USA 1997,94, 12053; and Kurihara et al., J. Exp. Med. 1997, 186, 1757.

Accordingly, agents that inhibit the interaction of MCP-1 and CCR2 wouldbe useful in the treatment of a variety of inflammatory, allergic andautoimmune diseases, disorders, or conditions.

DETAILED DESCRIPTION OF THE INVENTION 1. General Description ofCompounds of the Invention

The present invention provides compounds that are effective inhibitorsof CCR2. Accordingly, these compounds are useful for the treatment ofvarious cell inflammatory, allergic and autoimmune diseases, disorders,or conditions.

The present invention relates to a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   Y is -Y₁-Y₂-, wherein:    -   Y₁ is —SO₂N(R′)—, —C(O)N(R′)—; —C(O)N(R′)C(O)—, —N(R′)SO₂—,        —N(R′)SO₂N(R′)—, —N(R′)C(O)—, —NR′C(O)N(R′)—, or —N(R′)C(O)O—;        and    -   Y₂ is absent or is an optionally substituted C₁₋₆ alkylene        chain, wherein one or two methylene units of Y₂ are optionally        and independently interrupted by —O—, —S—, —N(R′)—, —C(O)—,        —OC(O)—, —C(O)O—, —S(O)—, —S(O)₂—, —C(O)N(R′)—, —N(R′)C(O)—,        —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —OC(O)N(R′)—, —N(R′)S(O)₂—, or        —S(O)₂N(R′)—, or wherein Y₂, or a portion thereof, is an        optionally substituted ring selected from 3-6-membered        cycloaliphatic, 3-6-membered heterocyclyl having 1-3 heteroatoms        independently selected from nitrogen, oxygen, or sulfur,        6-membered aryl, or 5-6-membered heteroaryl having 1-3        heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   each R′ is independently hydrogen or optionally substituted        C₁₋₆aliphatic;-   R¹ is an optionally substituted group selected from 3-10-membered    cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms    independently selected from nitrogen, oxygen, or sulfur,    6-10-membered aryl, or 5-10-membered heteroaryl having 1-5    heteroatoms independently selected from nitrogen, oxygen, or sulfur;-   ring A is substituted at one or more carbon atoms with m independent    occurrences of R²;-   m is 0-6;-   each occurrence of R² is independently halogen, ═O, ═S, —CN,    -R^(2b), N(R^(2a))₂, OR^(2a), SR^(2b), —S(O)₂R^(2b), —C(O)R^(2a),    C(O)OR^(2a), C(O)N(R^(2a))₂, —S(O)₂N(R^(2a))₂, —OC(O)N(R^(2a))₂,    —N(R′)C(O)R^(2a), —N(R′)SO₂R^(2b), —N(R′)C(O)OR^(2a),    —N(R′)C(O)N(R^(2a))₂, or —N(R′)SO₂N(R^(2a))₂, or two occurences of    R^(2a) or R^(2b) are optionally taken together with their    intervening atom(s) to form an optionally substituted spiro, fused,    or bridged ring selected from 6-membered aryl, 3-6-membered    cycloaliphatic, 3-7-membered heterocyclyl having 1-3 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, or    5-6-membered heteroaryl having 1-3 heteroatoms independently    selected from nitrogen, oxygen, or sulfur, or two occurrences of    R^(2a), taken together with the nitrogen atom to which they are    bound, form an optionally substituted 3-7-membered heterocyclyl ring    having 1-3 additional heteroatoms selected from nitrogen, oxygen, or    sulfur;    -   each occurrence of R^(2a) is independently hydrogen or an        optionally substituted group selected from C₁₋₆aliphatic,        3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   each occurrence of R^(2b) is independently an optionally        substituted group selected from C₁₋₆aliphatic, 3-10-membered        cycloaliphatic, 3-10-membered heterocyclyl having 1-5        heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;-   ring B is substituted with r independent occurrences of -R³;-   r is 0-6;-   each occurrence of R³ is independently -R^(3a), -T₁-R^(3d), or    —V₁-T₁-R^(3d), wherein:    -   each occurrence of -R^(3a) is independently halogen, —CN, —NO₂,        -R^(3c), —N(R^(3b))₂, —OR^(3b), —SR^(3c), —S(O)₂R^(3c),        —C(O)R^(3b), —C(O)OR^(3b), —C(O)N(R^(3b))₂, —S(O)₂N(R^(3b))₂,        —OC(O)N(R^(3b))₂, —N(R′)C(O)R^(3b), —N(R′)SO₂R^(3c),        —N(R′)C(O)OR^(3b), —N(R′)C(O)N(R^(3b))₂, or —N(R′)SO₂N(R^(3b))₂,        or two occurences of R^(3b) or R^(3c) are optionally taken        together with their intervening atom(s) to form an optionally        substituted spiro, fused, or bridged ring selected from        6-membered aryl, 3-6-membered cycloaliphatic, 3-7-membered        heterocyclyl having 1-3 heteroatoms independently selected from        nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having        1-3 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, or two occurrences of R^(3b), taken together with the        nitrogen atom to which they are bound, form an optionally        substituted 3-7-membered heterocyclyl ring having 1-3 additional        heteroatoms selected from nitrogen, oxygen, or sulfur;    -   each occurrence of R^(3b) is independently hydrogen or an        optionally substituted group selected from C₁₋₆aliphatic,        3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   each occurrence of R^(3c) is independently an optionally        substituted group selected from C₁₋₆aliphatic, 3-10-membered        cycloaliphatic, 3-10-membered heterocyclyl having 1-5        heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   each occurrence of R^(3d) is independently an optionally        substituted group selected from 3-10-membered cycloaliphatic,        3-10-membered heterocyclyl having 1-5 heteroatoms independently        selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl,        or 5-10-membered heteroaryl having 1-5 heteroatoms independently        selected from nitrogen, oxygen, or sulfur;    -   each occurrence of V₁ is independently —C(R′)═C(R′)—, —C—C—,        —N(R′)—, —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—,        —C(O)N(R′)—, —S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—,        —N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)SO₂N(R′)—,        —OC(O)—, or —C(O)N(R′)—O—;    -   each occurrence of T₁ is independently C₁₋₆ alkylene chain        optionally substituted with R^(3a), wherein the alkylene chain        optionally is interrupted by —C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—,        —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R′)—,        —S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO₂—,        —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)SO₂N(R′)—, —OC(O)—, or        —C(O)N(R′)—O— or wherein T¹ or a portion thereof optionally        forms part of an optionally substituted 3-7 membered        cycloaliphatic or heterocyclyl ring;-   X is —O—, —S—, —SO₂—, or —N(W—R⁴)—;-   W is absent or is a group selected from —W₁-L₂-W₂—, wherein W₁ and    W₂ are each independently absent or are an optionally substituted    C₁₋₃alkylene chain, and L₂ is absent or is a group selected from    —N(R)—, —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R)—,    —S(O)₂N(R)—, —OC(O)N(R)—, —N(R)C(O)—, —N(R)SO₂—, —N(R)C(O)O—,    —N(R)C(O)N(R)—, —N(R)SO₂N(R)—, —OC(O)—, or —C(O)N(R)—O—, wherein R    is hydrogen or C₁-C₄alkyl, provided that if W₁ is absent then L₂ is    selected from —C(O)—, —C(O)O—, —C(O)O—, —S(O)—, —S(O)₂—, —C(O)N(R)—,    or —S(O)₂N(R)—    -   R⁴ is an optionally substituted monocyclic or bicyclic ring        selected from 3-10-membered cycloaliphatic, 3-10-membered        heterocyclyl having 1-5 heteroatoms independently selected from        nitrogen, oxygen, or sulfur, 6-10-membered aryl, or        5-10-membered heteroaryl having 1-5 heteroatoms independently        selected from nitrogen, oxygen, or sulfur.

In some embodiments, a compound of the invention is other than one ormore of:

a) 1-Pyrrolidinecarboxamide,3-[6-(4-chlorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl]-N-methyl-N-[(3S)-1-(tetrahydro-2-oxo-3-furanyl)-3-pyrrolidinyl]-,(3S)—;

b) Pentitol,1,4-anhydro-2,3,5-trideoxy-3-[(3R)-3-[methyl[[(3S)-3-[methyl[[(4-phenoxyphenyl)amino]carbonyl]amino]-1-pyrrolidinyl]carbonyl]amino]-1-pyrrolidinyl]-;

c) 1-Pyrrolidinecarboxamide,N-methyl-3-[methyl[[4′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl]amino]-N-[(3R)-1′-(phenylmethyl)[1,3′-bipyrrolidin]-3-yl]-,(3S)—;

d) Pentitol,1,4-anhydro-2,3,5-trideoxy-3-[(3R)-3-[methyl[[(3S)-3-[methyl[[4′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl]amino]-1-pyrrolidinyl]carbonyl]amino]-1-pyrrolidinyl]-;

e) [1,3′-Bipyrrolidine]-1′-carboxylic acid,3-[(hydroxyamino)carbonyl]-4-[[4-[(2-methyl-4-quinolinyl)methoxy]benzoyl]amino]-,1,1-dimethylethyl ester, (3R,4R)-rel-; and

f) [1,3′-Bipyrrolidine]-3-carboxamide,N-hydroxy-4-[[4-[(2-methyl-4-quinolinyl)methoxy]benzoyl]amino]-,(3R,4R)-rel-.

2. Compounds and Definitions

Compounds of this invention include those described generally above, andare further illustrated by the classes, subclasses, and speciesdisclosed herein. As used herein, the following definitions shall applyunless otherwise indicated.

As described herein, compounds of the invention may be optionallysubstituted with one or more substituents, such as are illustratedgenerally above, or as exemplified by particular classes, subclasses,and species of the invention. It will be appreciated that the phrase“optionally substituted” is used interchangeably with the phrase“substituted or unsubstituted.” In general, the term “substituted”,whether preceded by the term “optionally” or not, means that a hydrogenradical of the designated moiety is replaced with the radical of aspecified substituent, provided that the substitution results in astable or chemically feasible compound. The term “substitutable”, whenused in reference to a designated atom, means that attached to the atomis a hydrogen radical, which can be replaced with the radical of asuitable substituent. Unless otherwise indicated, an “optionallysubstituted” group may have a substituent at each substitutable positionof the group, and when more than one position in any given structure maybe substituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds.

A stable compound or chemically feasible compound is one in which thechemical structure is not substantially altered when kept at atemperature from about −80° C. to about +400, in the absence of moistureor other chemically reactive conditions, for at least a week, or acompound which maintains its integrity long enough to be useful fortherapeutic or prophylactic administration to a patient. The phrase “oneor more substituents”, as used herein, refers to a number ofsubstituents that equals from one to the maximum number of substituentspossible based on the number of available bonding sites, provided thatthe above conditions of stability and chemical feasibility are met.

As used herein, the term “independently selected” means that the same ordifferent values may be selected for multiple instances of a givenvariable in a single compound. By way of example, in a compound offormula (I), if Ring B is substituted with two substituents -R^(b), eachsubstituent is selected from the group of defined values for R^(b), andthe two values selected may be the same or different.

The term “aliphatic” or “aliphatic group”, as used herein, means anoptionally substituted straight-chain or branched C₁₋₁₂ hydrocarbon, ora cyclic C₁₋₁₂ hydrocarbon which is completely saturated or whichcontains one or more units of unsaturation, but which is not aromatic(also referred to herein as “carbocycle”, “cycloaliphatic”,“cycloalkyl”, or “cycloalkenyl”). For example, suitable aliphatic groupsinclude optionally substituted linear, branched or cyclic alkyl,alkenyl, alkynyl groups and hybrids thereof, such as (cycloalkyl)alkyl,(cycloalkenyl)alkyl, or (cycloalkyl)alkenyl. Unless otherwise specified,in various embodiments, aliphatic groups have 1-12, 1-10, 1-8, 1-6, 1-4,1-3, or 1-2 carbon atoms.

The term “alkyl”, used alone or as part of a larger moiety, refers to anoptionally substituted straight or branched chain hydrocarbon grouphaving 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms.

The term “alkenyl”, used alone or as part of a larger moiety, refers toan optionally substituted straight or branched chain hydrocarbon grouphaving at least one double bond and having 2-12, 2-10, 2-8, 2-6, 2-4, or2-3 carbon atoms.

The term “alkynyl”, used alone or as part of a larger moiety, refers toan optionally substituted straight or branched chain hydrocarbon grouphaving at least one triple bond and having 2-12, 2-10, 2-8, 2-6, 2-4, or2-3 carbon atoms.

The terms “cycloaliphatic”, “carbocycle”, “carbocyclyl”, “carbocyclo”,or “carbocyclic”, used alone or as part of a larger moiety, refer to anoptionally substituted saturated or partially unsaturated cyclicaliphatic ring system having from 3 to about 14 ring carbon atoms. Insome embodiments, the cycloaliphatic group is an optionally substitutedmonocyclic hydrocarbon having 3-8 or 3-6 ring carbon atoms.Cycloaliphatic groups include, without limitation, optionallysubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl,cyclooctenyl, or cyclooctadienyl. The terms “cycloaliphatic”,“carbocycle”, “carbocyclyl”, “carbocyclo”, or “carbocyclic” also includeoptionally substituted bridged or fused bicyclic rings having 6-12,6-10, or 6-8 ring carbon atoms, wherein any individual ring in thebicyclic system has 3-8 ring carbon atoms.

The term “cycloalkyl” refers to an optionally substituted saturated ringsystem of about 3 to about 10 ring carbon atoms. Exemplary monocycliccycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and cycloheptyl.

The term “cycloalkenyl” refers to an optionally substituted non-aromaticmonocyclic or multicyclic ring system containing at least onecarbon-carbon double bond and having about 3 to about 10 carbon atoms.Exemplary monocyclic cycloalkenyl rings include cyclopentyl,cyclohexenyl, and cycloheptenyl.

The terms “haloaliphatic”, “haloalkyl”, “haloalkenyl” and “haloalkoxy”refer to an aliphatic, alkyl, alkenyl or alkoxy group, as the case maybe, which is substituted with one or more halogen atoms. As used herein,the term “halogen” or “halo” means F, Cl, Br, or I. The term“fluoroaliphatic” refers to a haloaliphatic wherein the halogen isfluoro, including perfluorinated aliphatic groups. Examples offluoroaliphatic groups include, without limitation, fluoromethyl,difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl,1,1,2-trifluoroethyl, 1,2,2-trifluoroethyl, and pentafluoroethyl.

The term “heteroatom” refers to one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR⁺ (as in N-substituted pyrrolidinyl)). The terms “aryl” and “ar-”,used alone or as part of a larger moiety, e.g., “aralkyl”, “aralkoxy”,or “aryloxyalkyl”, refer to an optionally substituted C₆₋₁₄ aromatichydrocarbon moiety comprising one to three aromatic rings. Preferably,the aryl group is a C₆₋₁₀ aryl group. Aryl groups include, withoutlimitation, optionally substituted phenyl, naphthyl, or anthracenyl. Theterms “aryl” and “ar-”, as used herein, also include groups in which anaryl ring is fused to one or more cycloaliphatic rings to form anoptionally substituted cyclic structure such as a tetrahydronaphthyl,indenyl, or indanyl ring. The term “aryl” may be used interchangeablywith the terms “aryl group”, “aryl ring”, and “aromatic ring”.

An “aralkyl” or “arylalkyl” group comprises an aryl group covalentlyattached to an alkyl group, either of which independently is optionallysubstituted. Preferably, the aralkyl group is C₆₋₁₀ arylC₁₋₆alkyl,including, without limitation, benzyl, phenethyl, and naphthylmethyl.

The terms “heteroaryl” and “heteroar-”, used alone or as part of alarger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer togroups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms;having 6, 10, or 14 π electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to five heteroatoms. A heteroarylgroup may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, ortricyclic, more preferably mono- or bicyclic. The term “heteroatom”refers to nitrogen, oxygen, or sulfur, and includes any oxidized form ofnitrogen or sulfur, and any quaternized form of a basic nitrogen. Forexample, a nitrogen atom of a heteroaryl may be a basic nitrogen atomand may also be optionally oxidized to the corresponding N-oxide. When aheteroaryl is substituted by a hydroxy group, it also includes itscorresponding tautomer. The terms “heteroaryl” and “heteroar-”, as usedherein, also include groups in which a heteroaromatic ring is fused toone or more aryl, cycloaliphatic, or heterocycloaliphatic rings.Nonlimiting examples of heteroaryl groups include thienyl, furanyl,pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl,isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl,naphthyridinyl, pteridinyl, indolyl, isoindolyl, benzothienyl,benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl,quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl,phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Theterm “heteroaryl” may be used interchangeably with the terms “heteroarylring”, “heteroaryl group”, or “heteroaromatic”, any of which termsinclude rings that are optionally substituted. The term “heteroaralkyl”refers to an alkyl group substituted by a heteroaryl, wherein the alkyland heteroaryl portions independently are optionally substituted.

As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocyclicradical”, and “heterocyclic ring” are used interchangeably and refer toa stable 3- to 8-membered monocyclic or 7-10-membered bicyclicheterocyclic moiety that is either saturated or partially unsaturated,and having, in addition to carbon atoms, one or more, preferably one tofour, heteroatoms, as defined above. When used in reference to a ringatom of a heterocycle, the term “nitrogen” includes a substitutednitrogen. As an example, in a saturated or partially unsaturated ringhaving 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, thenitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as inpyrrolidinyl), or NR⁺ (as in N-substituted pyrrolidinyl).

A heterocyclic ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of such saturatedor partially unsaturated heterocyclic radicals include, withoutlimitation, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiamorpholinyl. Aheterocyclyl group may be mono-, bi-, tri-, or polycyclic, preferablymono-, bi-, or tricyclic, more preferably mono- or bicyclic. The term“heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted. Additionally, a heterocyclic ring alsoincludes groups in which the heterocyclic ring is fused to one or morearyl rings.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond between ring atoms. Theterm “partially unsaturated” is intended to encompass rings havingmultiple sites of unsaturation, but is not intended to include aryl orheteroaryl moieties, as herein defined.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein n is apositive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from1 to 2, or from 2 to 3. An optionally substituted alkylene chain is apolymethylene group in which one or more methylene hydrogen atoms isreplaced with a substituent. Suitable substituents include thosedescribed below for a substituted aliphatic group. An alkylene chainalso may be substituted at one or more positions with an aliphatic groupor a substituted aliphatic group.

An alkylene chain also can be optionally interrupted by a functionalgroup. An alkylene chain is “interrupted” by a functional group when aninternal methylene unit is replaced with the functional group. Examplesof suitable “interrupting functional groups” include —C(R⁺)═C(R⁺)—,—C≡C—, —O—, —S—, —S(O)—, —S(O)₂—, —S(O)₂N(R⁺)—, —N(R⁺)—, —N(R⁺)CO—,—N(R⁺)C(O)N(R⁺)—, —N(R⁺)C(═NR⁺)—N(R⁺)—, —N(R⁺)—C(═NR⁺)—, —N(R⁺)CO₂—,—N(R⁺)SO₂—, —N(R⁺)SO₂N(R⁺)—, —OC(O)—, —OC(O)O—, —OC(O)N(R⁺)—, —C(O)—,—CO₂—, —C(O)N(R⁺)—, —C(O)—C(O)—, —C(═NR⁺)—N(R⁺)—, —C(NR⁺)═N—,—C(═NR⁺)—O—, —C(OR⁺)═N—, —C(R^(o))═N—O—, or —N(R⁺)—N(R⁺)—. Each R⁺,independently, is hydrogen or an optionally substituted aliphatic, aryl,heteroaryl, cycloaliphatic, or heterocyclyl group, or two independentoccurrences of R⁺ are taken together with their intervening atom(s) toform an optionally substituted 5-7-membered aryl, heteroaryl,cycloaliphatic, or heterocyclyl ring. Each R^(o) is an optionallysubstituted aliphatic, aryl, heteroaryl, cycloaliphatic, or heterocyclylgroup.

Examples of C₃₋₆ alkylene chains that have been “interrupted” with —O—include —CH₂OCH₂—, —CH₂—O—(CH₂)₂—, —CH₂—O—(CH₂)₃—, —CH₂—O—(CH₂)₄—,—(CH₂)₂OCH₂—, —(CH₂)₂—O—(CH₂)₂—, —(CH₂)₂—O—(CH₂)₃—, —(CH₂)₃—O—(CH₂)—,—(CH₂)₃—O—(CH₂)₂—, and —(CH₂)₄—O—(CH₂)—. Other examples of alkylenechains that are “interrupted” with functional groups include —CH₂ZCH₂—,—CH₂Z(CH₂)₂—, —CH₂Z(CH₂)₃—, —CH₂Z(CH₂)₄—, —(CH₂)₂ZCH₂—, —(CH₂)₂Z(CH₂)₂—,—(CH₂)₂Z(CH₂)₃—, —(CH₂)₃Z(CH₂)—, —(CH₂)₃Z(CH₂)₂—, and —(CH₂)₄Z(CH₂)—,wherein Z is one of the “interrupting” functional groups listed above.One of ordinary skill in the art will recognize that when an alkylenechain having an interruption is attached to a functional group, certaincombinations are not sufficiently stable for pharmaceutical use. Onlystable or chemically feasible compounds are within the scope of thepresent invention.

For purposes of clarity, all bivalent groups described herein,including, e.g., the alkylene chain linkers described above, areintended to be read from left to right, with a correspondingleft-to-right reading of the formula or structure in which the variableappears.

An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) orheteroaryl (including heteroaralkyl and heteroarylalkoxy and the like)group may contain one or more substituents and thus may be “optionallysubstituted”. In addition to the substituents defined above and herein,suitable substituents on the unsaturated carbon atom of an aryl orheteroaryl group also include and are generally selected from -halo,—NO₂, —CN, -R⁺, —C(R⁺)═C(R⁺)₂, —C≡C—R⁺, —OR⁺, —SR^(o), —S(O)R^(o),—SO₂R^(o), —SO₃R⁺, —SO₂N(R⁺)₂, —N(R⁺)₂, —NR⁺C(O)R⁺, —NR⁺C(S)R⁺,—NR⁺C(O)N(R⁺)₂, —NR⁺C(S)N(R⁺)₂, —N(R⁺)C(═NR⁺)—N(R⁺)₂,—N(R⁺)C(═NR⁺)—R^(o), —NR⁺CO₂R⁺, —NR⁺SO₂R^(o), —NR⁺SO₂N(R⁺)₂, —O—C(O)R⁺,—O—CO₂R⁺, —OC(O)N(R⁺)₂, —C(O)R⁺, —C(S)R^(o), —CO₂R⁺, —C(O)—C(O)R⁺,—C(O)N(R⁺)₂, —C(S)N(R⁺)₂, —C(O)N(R⁺)—OR⁺, —C(O)N(R⁺)C(═NR⁺)—N(R⁺)₂,—N(R⁺)C(═NR⁺)—N(R⁺)—C(O)R⁺, —C(═NR⁺)—N(R⁺)₂, —C(═NR⁺)—OR⁺,—N(R⁺)—N(R⁺)₂, —C(═NR⁺)—N(R⁺)—OR⁺, —C(R^(o))═N—OR⁺, —P(O)(R⁺)₂,—P(O)(OR⁺)₂, —O—P(O)—OR⁺, and —P(O)(NR⁺)—N(R⁺)₂, wherein R^(o) and R⁺are as defined above.

An aliphatic or heteroaliphatic group, or a non-aromatic carbycyclic orheterocyclic ring may contain one or more substituents and thus may be“optionally substituted”. Unless otherwise defined above and herein,suitable substituents on the saturated carbon of an aliphatic orheteroaliphatic group, or of a non-aromatic carbocyclic or heterocyclicring are selected from those listed above for the unsaturated carbon ofan aryl or heteroaryl group and additionally include the following: ═O,═S, ═C(R*)₂, ═N—N(R*)₂, ═N—OR*, ═N—NHC(O)R*, ═N—NHCO₂R^(o),═N—NHSO₂R^(o) or ═N—R* where each R* and R^(o) is defined above.

In addition to the substituents defined above and herein, optionalsubstituents on the nitrogen of a non-aromatic heterocyclic ring alsoinclude and are generally selected from -R⁺, —N(R⁺)₂, —C(O)R⁺, —C(O)OR⁺,—C(O)C(O)R⁺, —C(O)CH₂C(O)R⁺, —S(O)₂R⁺, —S(O)₂N(R⁺)₂, —C(S)N(R⁺)₂,—C(═NH)—N(R⁺)₂, or —N(R⁺)S(O)₂R⁺; wherein each R⁺ is defined above. Aring nitrogen atom of a heteroaryl or non-aromatic heterocyclic ringalso may be oxidized to form the corresponding N-hydroxy or N-oxidecompound. A nonlimiting example of such a heteroaryl having an oxidizedring nitrogen atom is N-oxidopyridyl.

As detailed above, in some embodiments, two independent occurrences ofR⁺ (or any other variable similarly defined in the specification andclaims herein), are taken together with their intervening atom(s) toform a monocyclic or bicyclic ring selected from 3-13-memberedcycloaliphatic, 3-12-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur.

Exemplary rings that are formed when two independent occurrences of R⁺(or any other variable similarly defined in the specification and claimsherein), are taken together with their intervening atom(s) include, butare not limited to the following: a) two independent occurrences of R⁺(or any other variable similarly defined in the specification or claimsherein) that are bound to the same atom and are taken together with thatatom to form a ring, for example, N(R⁺)₂, where both occurrences of R⁺are taken together with the nitrogen atom to form a piperidin-1-yl,piperazin-1-yl, or morpholin-4-yl group; and b) two independentoccurrences of R⁺ (or any other variable similarly defined in thespecification or claims herein) that are bound to different atoms andare taken together with both of those atoms to form a ring, for examplewhere a phenyl group is substituted with two occurrences of OR⁺

these two occurrences of R⁺ are taken together with the oxygen atoms towhich they are bound to form a fused 6-membered oxygen containing ring:

It will be appreciated that a variety of other rings (e.g., spiro andbridged rings) can be formed when two independent occurrences of R⁺ (orany other variable similarly defined in the specification and claimsherein) are taken together with their intervening atom(s) and that theexamples detailed above are not intended to be limiting.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, (Z) and (E) double bondisomers, and (Z) and (E) conformational isomers. Therefore, singlestereochemical isomers as well as enantiomeric, diastereomeric, andgeometric (or conformational) mixtures of the present compounds arewithin the scope of the invention. Unless otherwise stated, alltautomeric forms of the compounds of the invention are within the scopeof the invention. Additionally, unless otherwise stated, structuresdepicted herein are also meant to include compounds that differ only inthe presence of one or more isotopically enriched atoms. For example,compounds having the present structures except for the replacement ofhydrogen by deuterium or tritium, or the replacement of a carbon by a¹³C— or ¹⁴C-enriched carbon are within the scope of this invention. Suchcompounds are useful, for example, as analytical tools or probes inbiological assays.

It is to be understood that, when a disclosed compound has at least onechiral center, the present invention encompasses one enantiomer ofinhibitor free from the corresponding optical isomer, racemic mixture ofthe inhibitor and mixtures enriched in one enantiomer relative to itscorresponding optical isomer. When a mixture is enriched in oneenantiomer relative to its optical isomers, the mixture contains, forexample, an enantiomeric excess of at least 50%, 75%, 90%, 95% 99% or99.5%.

The enantiomers of the present invention may be resolved by methodsknown to those skilled in the art, for example by formation ofdiastereoisomeric salts which may be separated, for example, bycrystallization; formation of diastereoisomeric derivatives or complexeswhich may be separated, for example, by crystallization, gas-liquid orliquid chromatography; selective reaction of one enantiomer with anenantiomer-specific reagent, for example enzymatic esterification; orgas-liquid or liquid chromatography in a chiral environment, for exampleon a chiral support for example silica with a bound chiral ligand or inthe presence of a chiral solvent. Where the desired enantiomer isconverted into another chemical entity by one of the separationprocedures described above, a further step is required to liberate thedesired enantiomeric form. Alternatively, specific enantiomers may besynthesized by asymmetric synthesis using optically active reagents,substrates, catalysts or solvents, or by converting one enantiomer intothe other by asymmetric transformation.

When a disclosed compound has at least two chiral centers, the presentinvention encompasses a diastereomer free of other diastereomers, a pairof diastereomers free from other diasteromeric pairs, mixtures ofdiasteromers, mixtures of diasteromeric pairs, mixtures of diasteromersin which one diastereomer is enriched relative to the otherdiastereomer(s) and mixtures of diasteromeric pairs in which onediastereomeric pair is enriched relative to the other diastereomericpair(s). When a mixture is enriched in one diastereomer ordiastereomeric pair(s) relative to the other diastereomers ordiastereomeric pair(s), the mixture is enriched with the depicted orreferenced diastereomer or diastereomeric pair(s) relative to otherdiastereomers or diastereomeric pair(s) for the compound, for example,by a molar excess of at least 50%, 75%, 90%, 95% 99% or 99.5%.

The diastereoisomeric pairs may be separated by methods known to thoseskilled in the art, for example chromatography or crystallization andthe individual enantiomers within each pair may be separated asdescribed above. Specific procedures for chromatographically separatingdiastereomeric pairs of precursors used in the preparation of compoundsdisclosed herein are provided the examples herein.

3. Description of Exemplary Compounds

In certain exemplary embodiments n is 1 and the compound has thestructure of formula I-A-I or 1-A-ii:

In certain embodiments r is 0 or 1. In other embodiments, r is 1 and thecompound has the structure of formula I-B:

In yet other embodiments, r is 2 and the compound has the structure ofI-B-i:

wherein the two occurrences of R³, taken together, form an optionallysubstituted 3-6-membered spiro carbocyclic or heterocyclic ring.

In certain embodiments, R¹ is an optionally substituted aryl group. Inother embodiments, R¹ is an optionally substituted phenyl group. Instill other embodiments, R¹ is an optionally substituted 5-8-memberedmonocyclic or 7-10-membered bicyclic heterocyclyl or heteroaryl ringhaving 1-4 heteroatoms independently selected from N, O, or S. In yetother embodiments, R¹ is an optionally substituted group selected from:

In still other embodiments, R¹ is an optionally substituted groupselected from:

In some embodiments, R¹ is optionally substituted with 1-3 occurrencesof R^(1a), wherein each occurrence of R^(1a) is independently halogen,═O, ═S, —CN, —NO₂, -R^(1c), —N(R^(1b))₂, —OR^(1b), SR^(1c),—S(O)₂R^(1c), C(O)R^(1b), —C(O)OR^(1b), —C(O)N(R^(1b))₂,—S(O)₂N(R^(1b))₂, —OC(O)N(R^(1b))₂, —N(R′)C(O)R^(1b), N(R′)SO₂R^(1c),—N(R′)C(O)OR^(1b), N(R′)C(O)N(R^(1b))₂, or N(R′)SO₂N(R^(1b))₂, or twooccurences of R^(1b) or R^(1c) are optionally taken together with theirintervening atom(s) to form an optionally substituted spiro, fused, orbridged ring selected from 6-membered aryl, 3-6-membered cycloaliphatic,3-7-membered heterocyclyl having 1-3 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3heteroatoms independently selected from nitrogen, oxygen, or sulfur, ortwo occurrences of R^(1b), taken together with the nitrogen atom towhich they are bound, form an optionally substituted 3-7-memberedheterocyclyl ring having 1-3 additional heteroatoms selected fromnitrogen, oxygen, or sulfur, wherein:

-   -   each occurrence of R^(1b) is independently hydrogen or an        optionally substituted group selected from C₁₋₆aliphatic,        3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur; and    -   each occurrence of R^(1c) is independently an optionally        substituted group selected from C₁₋₆aliphatic, 3-10-membered        cycloaliphatic, 3-10-membered heterocyclyl having 1-5        heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur.

In some embodiments, each occurrence of R^(1a) is independently ═O,halogen, R^(1c), —N(R^(1b))₂, —OR^(1b), or —SR^(1c). In otherembodiments, each occurrence of R^(1a) is independentlyC₁₋₄-fluoroalkyl, —O(C₁₋₄-fluoroalkyl), or —S(C₁₋₄-fluoroalkyl).

In still other embodiments, Y₁ is —SO₂N(R′)—, —C(O)NR′—, or—N(R′)S(O)₂—.

In yet other embodiments, Y₁ is —N(R′)C(O)—. In still other embodiments,Y is selected from:

In other embodiments, for compounds of the invention X is O. In stillother embodiments, X is —N(W—R⁴).

In still other embodiments, for compounds of the invention, X is O, m is1, and R² is an optionally substituted group selected from a monocyclic3-8-membered heterocyclyl having 1-2 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, a bicyclic 7-10-membered heterocyclylhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, orsulfur, a monocyclic 5-6-membered heteroaryl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or a7-10-membered heteroaryl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

In yet other embodiments, for compounds of the invention, X is —N(W—R⁴)and R⁴ is an optionally substituted group selected from a monocyclic3-8-membered heterocyclyl having 1-2 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, a bicyclic 7-10-membered heterocyclylhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, orsulfur, a monocyclic 5-6-membered heteroaryl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or a7-10-membered heteroaryl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

In yet other embodiments, R⁴ is optionally substituted with 1-3occurrences of R^(4a) and each occurrence of R^(4a) is independently-R^(4b), -T₁-R^(4c), or —V₁-T₁-R^(4c), wherein:

-   -   each occurrence of -R^(4b) is independently halogen, —CN, —NO₂,        -R^(4d), —N(R)₂, OR^(4c), SR^(4d), —S(O)₂R^(4d), —C(O)R^(4c),        —C(O)OR^(4c), —C(O)N(R^(4c))₂, —S(O)₂N(R^(4c))₂,        —OC(O)N(R^(4c))₂, —N(R′)C(O)R^(4c), —N(R′)SO₂R^(4d),        —N(R′)C(O)OR^(4c), —N(R′)C(O)N(R^(4c))₂, or —N(R′)SO₂N(R^(4c))₂,        or two occurences of R^(4b), R^(4c) or R^(4d) are optionally        taken together with their intervening atom(s) to form an        optionally substituted spiro, fused, or bridged ring selected        from 6-membered aryl, 3-6-membered cycloaliphatic, 3-7-membered        heterocyclyl having 1-3 heteroatoms independently selected from        nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having        1-3 heteroatoms independently selected from nitrogen, oxygen, or        sulfur or two occurrences of R^(4c), taken together with the        nitrogen atom to which they are bound, form an optionally        substituted 3-7-membered heterocyclyl ring having 1-3 additional        heteroatoms selected from nitrogen, oxygen, or sulfur;    -   each occurrence of R^(4c) is independently hydrogen or an        optionally substituted group selected from C₁₋₆aliphatic,        3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   each occurrence of R^(4d) is independently an optionally        substituted group selected from C₁₋₆aliphatic, 3-10-membered        cycloaliphatic, 3-10-membered heterocyclyl having 1-5        heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   each occurrence of R^(4c) is independently an optionally        substituted group selected from 3-10-membered cycloaliphatic,        3-10-membered heterocyclyl having 1-5 heteroatoms independently        selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl,        or 5-10-membered heteroaryl having 1-5 heteroatoms independently        selected from nitrogen, oxygen, or sulfur;    -   each occurrence of V₁ is independently —C(R′)═C(R′)—, —C≡C—,        —N(R′)—, —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—,        —C(O)N(R′)—, —S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—,        —N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)SO₂N(R′)—,        —OC(O)—, or —C(O)N(R′)—O—;    -   each occurrence of T₁ is independently C₁₋₆ alkylene chain        optionally substituted with R^(3a), wherein the alkylene chain        optionally is interrupted by —C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—,        —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R′)—,        —S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO₂—,        —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)SO₂N(R′)—, —OC(O)—, or        —C(O)N(R′)—O— or wherein T¹ or a portion thereof optionally        forms part of an optionally substituted 3-7 membered        cycloaliphatic or heterocyclyl ring;

In still other embodiments, X is —N(W—R⁴), W is absent and R⁴ isoptionally substituted phenyl, wherein the phenyl group is substitutedwith 1 or 2 occurrences of R^(4a), wherein each occurrence of R^(4a) isindependently halogen, —CN, —C(O)N(R^(4c))₂, —O(R^(4c)), —S(R^(4d)),—N(R^(4c))₂, —C(O)O-T₁-R^(4c), -R^(4d), or wherein two occurrences ofR^(4b), taken together with their intervening atoms, form a 5-6-memberedspiro or fused carbocyclic or heterocyclyl ring.

In yet other embodiments, for compounds of the invention, R³ is—OR^(3b), —SR^(3c), —V₁-T₁-R^(3d), or T₁-R^(3d), wherein V₁ is O or S,and T₁ is —CH₂— or —CH₂—CH₂—.

In some embodiments, R^(3b), R^(3c), and R^(3d) are each independentlyan optionally substituted group selected from C₁₋₄alkenyl, C₁₋₄alkynyl,C₁₋₄alkyl, 5-10-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur.

In other embodiments, R^(3b), R^(3c), and R^(3d) are each independentlyoptionally substituted C₁₋₄alkenyl, C₁₋₄alkynyl, C₁₋₄alkyl, or anoptionally substituted group selected from:

In still other embodiments, R^(3b), R^(3c), and R^(3d) are eachindependently an optionally substituted ring selected from bicyclic8-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur or 8-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In yet other embodiments, R^(3b), R^(3c), and R^(3d) are eachindependently optionally substituted with 1-3 occurrences of R³, whereinR^(3e) is R^(f), halogen, N(R^(g))₂, —SR^(f), —S(O)₂R^(f), —COR^(f),—COOR^(g), —CON(R^(g))₂, —CON(R^(g))₂, —S(O)₂N(R^(g))₂, —CC(O)N(R^(g))₂,—NR′C(O)R^(f), —NR′S(O)₂R^(f), wherein R^(f) is an optionallysubstituted C₁₋₆ aliphatic group and R^(g) is hydrogen or an optionallysubstituted C₁₋₆ aliphatic group.

In still other embodiments, R^(3b), R^(3c), and R^(3d) are eachindependently optionally substituted with 1-3 occurrences of R^(3e),wherein R^(3e) is C₁₋₄aliphatic, C₁₋₄haloaliphatic, or halogen.

In still other embodiments, r is 2 and two occurrences of R³, takentogether, form an optionally substituted 3-6-membered spiro carbocyclicor heterocyclic ring. In some embodiments, the spiro ring is anoptionally substituted ring selected from:

Certain additional subsets of interest include those compounds havingthe structure of formula I-C:

or a pharmaceutically acceptable salt thereof.

In some embodiments, for compounds of general formula I-C, X is O andthe compound has the structure of formula I-D:

or a pharmaceutically acceptable salt thereof, wherein:

a) R¹ is an optionally substituted 5-8-membered monocyclic or7-10-membered bicyclic heterocyclyl or heteroaryl ring having 1-4heteroatoms independently selected from N, O, or S, wherein R¹ isoptionally substituted with 1-3 occurrences of R^(1a), wherein eachoccurrence of R^(1a) is independently halogen, ═O, ═S, —CN, —NO₂,-R^(1c), —N(R^(1b))₂, —OR^(1b), —SR^(1c), —S(O)₂R^(1c), C(O)R^(1b),C(O)OR^(1b), C(O)N(R^(1b))₂—S(O)₂N(R^(1b))₂, —OC(O)N(R^(1b))₂,—N(R′)C(O)R^(1b), —N(R′)SO₂R^(1c), —N(R′)C(O)OR^(1b),—N(R′)C(O)N(R^(1b))₂, or —N(R′)SO₂N(R^(1b))₂, or two occurences ofR^(1b) or R^(1c) are optionally taken together with their interveningatom(s) to form an optionally substituted spiro, fused, or bridged ringselected from 6-membered aryl, 3-6-membered cycloaliphatic, 3-7-memberedheterocyclyl having 1-3 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3heteroatoms independently selected from nitrogen, oxygen, or sulfur ortwo occurrences of R^(1b), taken together with the nitrogen atom towhich they are bound, form an optionally substituted 3-7-memberedheterocyclyl ring having 1-3 additional heteroatoms selected fromnitrogen, oxygen, or sulfur, wherein:

-   -   each occurrence of R^(1b) is independently hydrogen or an        optionally substituted group selected from C₁₋₆aliphatic,        3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur; and    -   each occurrence of R^(1c) is independently an optionally        substituted group selected from C₁₋₆aliphatic, 3-10-membered        cycloaliphatic, 3-10-membered heterocyclyl having 1-5        heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;

b) Y is —NH(CO)CH₂—, —NHS(O)₂CH₂, —NHC(O)—, —NH(CO)CH₂NH—, or —NHS(O)₂—;

c) m is 0 or 1, and when m is 1 R² is an optionally substituted groupselected from a monocyclic 3-7-membered heterocyclyl having 1-2heteroatoms independently selected from nitrogen, oxygen, or sulfur, abicyclic 7-10-membered heterocyclyl having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, a monocyclic 5-6-memberedheteroaryl having 1-3 heteroatoms independently selected from nitrogen,oxygen, or sulfur, or a 7-10-membered heteroaryl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; and

d) R³ is —OR^(3b), —SR^(3c), —V₁-T₁-R^(3d), or T₁-R^(3d), wherein V₁ isO or S, and T₁ is —CH₂— or —CH₂—CH₂—, wherein R^(3b), R^(3c), and R^(3d)are each independently an optionally substituted group selected fromC₁₋₄alkenyl, C₁₋₄alkynyl, C₁₋₄alkyl, 5-10-membered heterocyclyl having1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur,6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

In other embodiments, for compounds of general formula I-D:

a) R¹ is an optionally substituted group selected from:

and each occurrence of R^(1a) is independently ═O, halogen, -R^(1c),—N(R^(1b))₂, —OR^(1b), or SR^(1c); andb) R^(3b), R^(3c), and R^(3d) are each independently optionallysubstituted C₁₋₄alkenyl, C₁₋₄alkynyl, C₁₋₄alkyl, or an optionallysubstituted group selected from:

wherein R^(3b), R^(3c), and R^(3d) are each independently optionallysubstituted with 1-3 occurrences of R^(3e), wherein R³, isC₁₋₄aliphatic, C₁₋₄haloaliphatic, or halogen.

In some embodiments, for compounds of general formula I-C, X is N(W—R⁴),and the compound has the structure of formula I-E:

or a pharmaceutically acceptable salt thereof, wherein:

a) R¹ is an optionally substituted 5-8-membered monocyclic or7-10-membered bicyclic heterocyclyl or heteroaryl ring having 1-4heteroatoms independently selected from N, O, or S, wherein R¹ isoptionally substituted with 1-3 occurrences of R^(1a), wherein eachoccurrence of R^(1a) is independently halogen, ═O, —CN, —NO₂, -R^(1c),—N(R^(1b))₂, —OR^(1b), —SR^(1c), —S(O)₂R^(1c), —C(O)R^(1b),—C(O)OR^(1b), —C(O)N(R^(1b))₂, —S(O)₂N(R^(1b))₂, —OC(O)N(R^(1b))₂,—N(R′)C(O)R^(1b), —N(R′)SO₂R^(1c), —N(R′)C(O)OR^(1b),—N(R′)C(O)N(R^(1b))₂, or —N(R′)SO₂N(R^(1b))₂, or two occurences ofR^(1b) or R^(1c) are optionally taken together with their interveningatom(s) to form an optionally substituted spiro, fused, or bridged ringselected from 6-membered aryl, 3-6-membered cycloaliphatic, 3-7-memberedheterocyclyl having 1-3 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3heteroatoms independently selected from nitrogen, oxygen, or sulfur ortwo occurrences of R^(1b), taken together with the nitrogen atom towhich they are bound, form an optionally substituted 3-7-memberedheterocyclyl ring having 1-3 additional heteroatoms selected fromnitrogen, oxygen, or sulfur, wherein:

-   -   each occurrence of R^(1b) is independently hydrogen or an        optionally substituted group selected from C₁₋₆aliphatic,        3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur; and    -   each occurrence of R^(1c) is independently an optionally        substituted group selected from C₁₋₆aliphatic, 3-10-membered        cycloaliphatic, 3-10-membered heterocyclyl having 1-5        heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;

b) Y is —NH(CO)CH₂—, —NHS(O)₂CH₂, —NHC(O)—, —NH(CO)CH₂NH—, or —NHS(O)₂—;

c) m is 0;

d) R³ is —OR^(3b), —SR^(3c), —V₁-T₁-R^(3d), or T₁-R^(3d), wherein V₁ isO or S, and T₁ is —CH₂— or —CH₂—CH₂—, wherein R^(3b), R^(3c), and R^(3d)are each independently an optionally substituted group selected fromC₁₋₄alkenyl, C₁₋₄alkynyl, C₁₋₄alkyl, 5-10-membered heterocyclyl having1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur,6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur;

e) W is absent, and

f) R⁴ is an optionally substituted group selected from a monocyclic3-7-membered heterocyclyl having 1-2 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, a bicyclic 7-10-membered heterocyclylhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, orsulfur, a monocyclic 5-6-membered heteroaryl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or a7-10-membered heteroaryl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

In some embodiments, for compounds of general formula I-C, X is N(W—R⁴),and the compound has the structure of formula I-E:

or a pharmaceutically acceptable salt thereof, wherein:

a) R¹ is an optionally substituted 5-8-membered monocyclic or7-10-membered bicyclic heterocyclyl or heteroaryl ring having 1-4heteroatoms independently selected from N, O, or S, wherein R¹ isoptionally substituted with 1-3 occurrences of R^(1a), wherein eachoccurrence of R^(1a) is independently halogen, ═O, —CN, —NO₂, -R^(1c),—N(R^(1b))₂, —OR^(1b), —SR^(1c), —S(O)₂R^(1c), —C(O)R^(1b),—C(O)OR^(1b), C(O)N(R^(1b))₂, —S(O)₂N(R^(1b))₂, —OC(O)N(R^(1b))₂,—N(R′)C(O)R^(1b), —N(R′)SO₂R^(1c), —N(R′)C(O)OR^(1b),—N(R′)C(O)N(R^(1b))₂, or —N(R′)SO₂N(R^(1b))₂, or two occurences ofR^(1b) or R^(1c) are optionally taken together with their interveningatom(s) to form an optionally substituted spiro, fused, or bridged ringselected from 6-membered aryl, 3-6-membered cycloaliphatic, 3-7-memberedheterocyclyl having 1-3 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3heteroatoms independently selected from nitrogen, oxygen, or sulfur ortwo occurrences of R^(1b), taken together with the nitrogen atom towhich they are bound, form an optionally substituted 3-7-memberedheterocyclyl ring having 1-3 additional heteroatoms selected fromnitrogen, oxygen, or sulfur, wherein:

-   -   each occurrence of R^(1b) is independently hydrogen or an        optionally substituted group selected from C₁₋₆aliphatic,        3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur; and    -   each occurrence of R^(1c) is independently an optionally        substituted group selected from C₁₋₆aliphatic, 3-10-membered        cycloaliphatic, 3-10-membered heterocyclyl having 1-5        heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;

b) Y is —NH(CO)CH₂—, —NHS(O)₂CH₂, —NHC(O)—, —NH(CO)CH₂NH—, or —NHS(O)₂—;

c) m is 0;

d) R³ is —OR^(3b), —SR^(3c), —V₁-T₁-R^(3d), or T₁-R^(3d), wherein V₁ isO or S, and T₁ is —CH₂— or —CH₂—CH₂—, wherein R^(3b), R^(3c), and R^(3d)are each independently an optionally substituted group selected fromC₁₋₄alkenyl, C₁₋₄alkynyl, C₁₋₄alkyl, 5-10-membered heterocyclyl having1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur,6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur;

e) W is absent, and

f) R⁴ is optionally substituted phenyl.

In other embodiments, for compounds of general formula I-E, R⁴ isoptionally substituted with 1-3 occurrences of R^(4a) and eachoccurrence of R^(4a) is independently -R^(4b), -T₁-R^(1e), or—V₁-T₁-R^(1e), wherein:

-   -   each occurrence of -R^(4b) is independently halogen, —CN, —NO₂,        R^(4d), —N(R^(4c))₂, —OR^(4c), —SR^(4d), —S(O)₂R^(4d),        —C(O)R^(4c), —C(O)OR^(4c), —C(O)N(R^(4c))₂, —S(O)₂N(R^(4c))₂,        —OC(O)N(R^(4c))₂, —N(R′)C(O)R^(4c), —N(R′)SO₂R^(4d),        —N(R′)C(O)OR^(4c), —N(R′)C(O)N(R^(4c))₂, or —N(R′)SO₂N(R^(4c))₂,        or two occurences of R^(4b), R^(4e) or R^(4d) are optionally        taken together with their intervening atom(s) to form an        optionally substituted spiro, fused, or bridged ring selected        from 6-membered aryl, 3-6-membered cycloaliphatic, 3-7-membered        heterocyclyl having 1-3 heteroatoms independently selected from        nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having        1-3 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, or two occurrences of R^(4c), taken together with the        nitrogen atom to which they are bound, form an optionally        substituted 3-7-membered heterocyclyl ring having 1-3 additional        heteroatoms selected from nitrogen, oxygen, or sulfur;    -   each occurrence of R^(4c) is independently hydrogen or an        optionally substituted group selected from C₁₋₆aliphatic,        3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   each occurrence of R^(4d) is independently an optionally        substituted group selected from C₁₋₆aliphatic, 3-10-membered        cycloaliphatic, 3-10-membered heterocyclyl having 1-5        heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   each occurrence of R^(4c) is independently an optionally        substituted group selected from 3-10-membered cycloaliphatic,        3-10-membered heterocyclyl having 1-5 heteroatoms independently        selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl,        or 5-10-membered heteroaryl having 1-5 heteroatoms independently        selected from nitrogen, oxygen, or sulfur;    -   each occurrence of V₁ is independently —C(R′)═C(R′)—, —C≡C—,        —N(R′)—, —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—,        —C(O)N(R′)—, —S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—,        —N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)SO₂N(R′)—,        —OC(O)—, or —C(O)N(R′)—O—; and    -   each occurrence of T₁ is independently C₁₋₆ alkylene chain        optionally substituted with R^(3a), wherein the alkylene chain        optionally is interrupted by —C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—,        —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R′)—,        —S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO₂—,        —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)SO₂N(R′)—, —OC(O)—, or        —C(O)N(R′)—O— or wherein T¹ or a portion thereof optionally        forms part of an optionally substituted 3-7 membered        cycloaliphatic or heterocyclyl ring.        In other embodiments, for compounds of general formula I-E:        a) R¹ is an optionally substituted group selected from:

and each occurrence of R^(1a) is independently ═O, halogen, R^(1c),—N(R^(1b))₂, —OR^(1b), or SR^(1c); andb) R^(3b), R^(3c), and R^(3d) are each independently optionallysubstituted C₁₋₄alkenyl, C₁₋₄alkynyl, C₁₋₄alkyl, or an optionallysubstituted group selected from:

wherein R^(3b), R^(3c), and R^(3d) are each independently optionallysubstituted with 1-3 occurrences of R^(3e), wherein R^(3e) isC₁₋₄aliphatic, C₁₋₄haloaliphatic, or halogen.

Still other subsets of interest include those compounds having thestructure of formula I-F:

or a pharmaceutically acceptable salt thereof,

wherein the two occurrences of R³, taken together, form an optionallysubstituted 3-6-membered spiro carbocyclic or heterocyclic ring.

In some embodiments, for compounds of general formula I-F, X is O andthe compound has the structure of formula I-G:

or a pharmaceutically acceptable salt thereof, wherein:

a) R¹ is an optionally substituted 5-8-membered monocyclic or7-10-membered bicyclic heterocyclyl or heteroaryl ring having 1-4heteroatoms independently selected from N, O, or S, wherein R¹ isoptionally substituted with 1-3 occurrences of R^(1a), wherein eachoccurrence of R^(1a) is independently halogen, ═O, ═S, —CN, —NO₂,R^(1c), —N(R^(1b))₂, —OR^(1b), —SR^(1c), —S(O)₂R^(1c), —C(O)R^(1b),—C(O)OR^(1b), C(O)N(R^(1b))₂, —S(O)₂N(R^(1b))₂, —OC(O)N(R^(1b))₂,—N(R′)C(O)R^(1b), —N(R′)SO₂R^(1c), —N(R′)C(O)OR^(1b),N(R′)C(O)N(R^(1b))₂, or —N(R′)SO₂N(R^(1b))₂, or two occurences of R^(1b)or R^(1c) are optionally taken together with their intervening atom(s)to form an optionally substituted spiro, fused, or bridged ring selectedfrom 6-membered aryl, 3-6-membered cycloaliphatic, 3-7-memberedheterocyclyl having 1-3 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3heteroatoms independently selected from nitrogen, oxygen, or sulfur ortwo occurrences of R^(1b), taken together with the nitrogen atom towhich they are bound, form an optionally substituted 3-7-memberedheterocyclyl ring having 1-3 additional heteroatoms selected fromnitrogen, oxygen, or sulfur, wherein:

-   -   each occurrence of R^(1b) is independently hydrogen or an        optionally substituted group selected from C₁₋₆aliphatic,        3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur; and    -   each occurrence of R^(1c) is independently an optionally        substituted group selected from C₁₋₆aliphatic, 3-10-membered        cycloaliphatic, 3-10-membered heterocyclyl having 1-5        heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;

b) Y is —NH(CO)CH₂—, —NHS(O)₂CH₂, —NHC(O)—, —NH(CO)CH₂NH—, or —NHS(O)₂—;

c) m is 0 or 1, and when m is 1 R² is an optionally substituted groupselected from a monocyclic 3-7-membered heterocyclyl having 1-2heteroatoms independently selected from nitrogen, oxygen, or sulfur, abicyclic 7-10-membered heterocyclyl having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, a monocyclic 5-6-memberedheteroaryl having 1-3 heteroatoms independently selected from nitrogen,oxygen, or sulfur, or a 7-10-membered heteroaryl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; and

d) wherein the two occurrences of R³, taken together, form an optionallysubstituted 3-6-membered spiro carbocyclic or heterocyclic ring.

In other embodiments, for compounds of general formula I-G:

a) R¹ is an optionally substituted group selected from:

and each occurrence of R^(1a) is independently ═O, halogen, -R^(1c),—N(R^(1b))₂, —OR^(1b), or —SR^(1c); andb) the Spiro ring formed from the two occurrences of R³ is an optionallysubstituted ring selected from:

In some embodiments, for compounds of general formula I-F, X is N(W—R⁴),and the compound has the structure of formula I-H:

or a pharmaceutically acceptable salt thereof, wherein:

a) R¹ is an optionally substituted 5-8-membered monocyclic or7-10-membered bicyclic heterocyclyl or heteroaryl ring having 1-4heteroatoms independently selected from N, O, or S, wherein R¹ isoptionally substituted with 1-3 occurrences of R^(1a), wherein eachoccurrence of R^(1a) is independently halogen, ═O, —CN, —NO₂, -R^(1c),—N(R^(1b))₂, —OR^(1b), —SR^(1c), —S(O)₂R^(1c), —C(O)R^(1b),—C(O)OR^(1b), C(O)N(R^(1b))₂, —S(O)₂N(R^(1b))₂, —OC(O)N(R^(1b))₂,—N(R′)C(O)R^(1b), —N(R′)SO₂R^(1c), —N(R′)C(O)OR^(1b),—N(R′)C(O)N(R^(1b))₂, or —N(R′)SO₂N(R^(1b))₂, or two occurences ofR^(1b) or R^(1c) are optionally taken together with their interveningatom(s) to form an optionally substituted spiro, fused, or bridged ringselected from 6-membered aryl, 3-6-membered cycloaliphatic, 3-7-memberedheterocyclyl having 1-3 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3heteroatoms independently selected from nitrogen, oxygen, or sulfur ortwo occurrences of R^(1b), taken together with the nitrogen atom towhich they are bound, form an optionally substituted 3-7-memberedheterocyclyl ring having 1-3 additional heteroatoms selected fromnitrogen, oxygen, or sulfur, wherein:

-   -   each occurrence of R^(1b) is independently hydrogen or an        optionally substituted group selected from C₁₋₆aliphatic,        3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur; and    -   each occurrence of R^(1c) is independently an optionally        substituted group selected from C₁₋₆aliphatic, 3-10-membered        cycloaliphatic, 3-10-membered heterocyclyl having 1-5        heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;

b) Y is —NH(CO)CH₂—, —NHS(O)₂CH₂, —NHC(O)—, —NH(CO)CH₂NH—, or —NHS(O)₂—;

c) m is 0;

d) wherein the two occurrences of R³, taken together, form an optionallysubstituted 3-6-membered spiro carbocyclic or heterocyclic ring;

e) W is absent, and

f) R⁴ is an optionally substituted group selected from a monocyclic3-7-membered heterocyclyl having 1-2 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, a bicyclic 7-10-membered heterocyclylhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, orsulfur, a monocyclic 5-6-membered heteroaryl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or a7-10-membered heteroaryl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

In some embodiments, for compounds of general formula I-F, X is N(W—R⁴),and the compound has the structure of formula I-H:

or a pharmaceutically acceptable salt thereof, wherein:

a) R¹ is an optionally substituted 5-8-membered monocyclic or7-10-membered bicyclic heterocyclyl or heteroaryl ring having 1-4heteroatoms independently selected from N, O, or S, wherein R¹ isoptionally substituted with 1-3 occurrences of R^(1a), wherein eachoccurrence of R^(1a) is independently halogen, ═O, —CN, —NO₂, -R^(1c),—N(R^(1b))₂, —OR^(1b), —SR^(1c), S(O)₂R^(1c), C(O)R^(1b), C(O)OR^(1b),—C(O)N(R^(1b))₂, —S(O)₂N(R^(1b))₂, —OC(O)N(R^(1b))₂, —N(R′)C(O)R^(1b),—N(R′)SO₂R^(1c), —N(R′)C(O)OR^(1b), —N(R′)C(O)N(R^(1b))₂, or—N(R′)SO₂N(R^(1b))₂, or two occurences of R^(1b) or R^(1c) areoptionally taken together with their intervening atom(s) to form anoptionally substituted spiro, fused, or bridged ring selected from6-membered aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclylhaving 1-3 heteroatoms independently selected from nitrogen, oxygen, orsulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur or two occurrences of R^(1b),taken together with the nitrogen atom to which they are bound, form anoptionally substituted 3-7-membered heterocyclyl ring having 1-3additional heteroatoms selected from nitrogen, oxygen, or sulfur,wherein:

-   -   each occurrence of R^(1b) is independently hydrogen or an        optionally substituted group selected from C₁₋₆aliphatic,        3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur; and    -   each occurrence of R^(1c) is independently an optionally        substituted group selected from C₁₋₆aliphatic, 3-10-membered        cycloaliphatic, 3-10-membered heterocyclyl having 1-5        heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;

b) Y is —NH(CO)CH₂—, —NHS(O)₂CH₂, —NHC(O)—, —NH(CO)CH₂NH—, or —NHS(O)₂—;

c) m is 0;

d) the spiro ring formed from the two occurrences of R³ is an optionallysubstituted ring selected from:

e) W is absent, and

f) R⁴ is optionally substituted phenyl.

In other embodiments, for compounds of general formula I-H, R⁴ isoptionally substituted with 1-3 occurrences of R^(4a) and eachoccurrence of R^(4a) is independently -R^(4b), -T₁-R^(4e), or—V₁-T₁-R^(4e), wherein:

-   -   each occurrence of -R^(4b) is independently halogen, —CN, —NO₂,        R^(4d), —N(R^(4c))₂, —OR^(4c), —SR^(4d), —S(O)₂R^(4d),        —C(O)R^(4c), —C(O)OR^(4c), —C(O)N(R^(4c))₂, —S(O)₂N(R^(4c))₂,        —OC(O)N(R^(4c))₂, —N(R′)C(O)R^(4c), —N(R′)SO₂R^(4d),        —N(R′)C(O)OR^(e), —N(R′)C(O)N(R^(4c))₂, or —N(R′)SO₂N(R^(4c))₂,        or two occurences of R^(4b), R^(4c) or R^(4d) are optionally        taken together with their intervening atom(s) to form an        optionally substituted spiro, fused, or bridged ring selected        from 6-membered aryl, 3-6-membered cycloaliphatic, 3-7-membered        heterocyclyl having 1-3 heteroatoms independently selected from        nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having        1-3 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, or two occurrences of R^(4c), taken together with the        nitrogen atom to which they are bound, form an optionally        substituted 3-7-membered heterocyclyl ring having 1-3 additional        heteroatoms selected from nitrogen, oxygen, or sulfur;    -   each occurrence of R^(4c) is independently hydrogen or an        optionally substituted group selected from C₁₋₆aliphatic,        3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   each occurrence of R^(4d) is independently an optionally        substituted group selected from C₁₋₆aliphatic, 3-10-membered        cycloaliphatic, 3-10-membered heterocyclyl having 1-5        heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   each occurrence of R^(4e) is independently an optionally        substituted group selected from 3-10-membered cycloaliphatic,        3-10-membered heterocyclyl having 1-5 heteroatoms independently        selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl,        or 5-10-membered heteroaryl having 1-5 heteroatoms independently        selected from nitrogen, oxygen, or sulfur;    -   each occurrence of V₁ is independently —C(R′)═C(R′)—, —C≡C—,        —N(R′)—, —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—,        —C(O)N(R′)—, —S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—,        —N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)SO₂N(R′)—,        —OC(O)—, or —C(O)N(R′)—O—; and    -   each occurrence of T₁ is independently C₁₋₆ alkylene chain        optionally substituted with R^(3a), wherein the alkylene chain        optionally is interrupted by —C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—,        —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R′)—,        —S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO₂—,        —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)SO₂N(R′)—, —OC(O)—, or        —C(O)N(R′)—O— or wherein T¹ or a portion thereof optionally        forms part of an optionally substituted 3-7 membered        cycloaliphatic or heterocyclyl ring.

In other embodiments, for compounds of general formula I-H:

a) R¹ is an optionally substituted group selected from:

and each occurrence of R^(1a) is independently —O, halogen, R^(1c),—N(R^(1b))₂, —OR^(1b), or SR^(1c); andb) the spiro ring formed from the two occurrences of R³ is an optionallysubstituted ring selected from:

4. Uses, Formulation, and Administration

As discussed above, the present invention provides compounds that areinhibitors of chemokine receptor activity. In some embodiments, thepresent invention provides compounds that are inhibitors of CCR2activity. The compounds can be assayed in vitro or in vivo for theirability to bind to and/or inhibit chemokine receptor activity,preferably CCR2. Assays are described in the Examples and/or are knownin the art.

In another aspect, therefore, the invention provides a method forinhibiting CCR2 activity in biological sample or a subject, which methodcomprises administering to the subject, or contacting said biologicalsample with a compound of formula I or a composition comprising saidcompound. The term “biological sample”, as used herein, includes,without limitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof; and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.Inhibition of CCR2 activity in a biological sample is useful for avariety of purposes that are known to one of skill in the art. Examplesof such purposes include, but are not limited to, blood transfusion,organ-transplantation, biological specimen storage, and biologicalassays.

In some embodiments, the compound of formula I interacts with andreduces the activity of more than one chemokine receptor in thebiological sample, preferably a cell. By way of example, when assayedagainst CCR2, some compounds of formula I show inhibition of more thanone chemokine receptor, for example CCR5. In some embodiments, thecompound of formula I is selective for the inhibition of CCR2, i.e., theconcentration of the compound that is required for inhibition of CCR2 islower, preferably at least 2-fold, 5-fold, 10-fold, or 50-fold lower,than the concentration of the compound required for inhibition ofanother chemokine receptor (e.g., CCR5). In some embodiments of theinvention, compounds of the invention are selective for the inhibitionof CCR2. As used herein, the term “selective” means that a compoundbinds to or inhibits a chemokine receptor with greater affinity orpotency, respectively, compared to at least one other chemokinereceptor, or preferably compared to all other chemokine receptors of thesame class (e.g., all of the CC-type receptors). In some embodiments,the compounds of the invention have binding or inhibition selectivityfor CCR2 or CCR5 over any other chemokine receptor. Selectivity can beat least about 10-fold, at least about 20-fold, at least about 50-fold,at least about 100-fold, at least about 200-fold, at least about500-fold, or at least about 1000-fold. Binding affinity and inhibitorpotency can be measured according to routine methods in the art, such asaccording to the assays provided herein.

As used herein the term “contacting” refers to the bringing together ofindicated moieties in an in vitro or an in vivo system. For example,“contacting” the chemokine receptor with a compound of the inventionincludes the administration of a compound of the present invention to asubject, such as a human, having a chemokine receptor, as well as, forexample, introducing a compound of the invention into a samplecontaining a cellular or purified preparation containing the chemokinereceptor.

In another aspect, the invention provides a pharmaceutical compositioncomprising a compound of formula (I) as defined above, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

If pharmaceutically acceptable salts of the compounds of the inventionare utilized in these compositions, the salts preferably are derivedfrom inorganic or organic acids and bases. For reviews of suitablesalts, see, e.g., Berge et al, J. Pharm. Sci. 66:1-19 (1977) andRemington: The Science and Practice of Pharmacy, 20th Ed., ed. A.Gennaro, Lippincott Williams & Wilkins, 2000.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. A“pharmaceutically acceptable salt” means any non-toxic salt of acompound of this invention that, upon administration to a recipient, iscapable of providing, either directly or indirectly, a compound of thisinvention or an active metabolite or residue thereof. As used herein,the term “active metabolite or residue thereof” means that a metaboliteor residue thereof is useful for the treatment of inflammatory orallergic disorders. In some embodiments, without wishing to be bound byany particular theory, a “pharmaceutically acceptable salt” means anynon-toxic salt of a compound of this invention that, upon administrationto a recipient, is capable of providing, either directly or indirectly,an inhibitorily active compound of the invention or an inhibitorilyactive metabolite or residue thereof. As used herein, the term“inhibitorily active compound or inhibitorily active metabolite orresidue thereof” means that a compound or metabolite or residue thereofis also an inhibitor of CCR2.

Nonlimiting examples of suitable acid addition salts include thefollowing: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, lucoheptanoate, glycerophosphate, hemisulfate,heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate,2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate,persulfate, 3-phenyl-propionate, picrate, pivalate, propionate,succinate, tartrate, thiocyanate, tosylate and undecanoate.

Suitable base addition salts include, without limitation, ammoniumsalts, alkali metal salts, such as sodium and potassium salts, alkalineearth metal salts, such as calcium and magnesium salts, salts withorganic bases, such as dicyclohexylamine salts, N-methyl-D-glucamine,and salts with amino acids such as arginine, lysine, and so forth.

Also, basic nitrogen-containing groups may be quaternized with suchagents as lower alkyl halides, such as methyl, ethyl, propyl, and butylchloride, bromides and iodides; dialkyl sulfates, such as dimethyl,diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl,lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkylhalides, such as benzyl and phenethyl bromides and others. Water oroil-soluble or dispersible products are thereby obtained.

As described above, the pharmaceutical compositions of the presentinvention additionally comprise a pharmaceutically acceptable carrier,which, as used herein, includes any and all solvents, diluents, or otherliquid vehicle, dispersion or suspension aids, surface active agents,isotonic agents, thickening or emulsifying agents, preservatives, solidbinders, lubricants and the like, as suited to the particular dosageform desired. Remington's Pharmaceutical Sciences, Mack Publishing Co.,a standard reference text in this field, discloses various carriers usedin formulating pharmaceutical compositions and known techniques for thepreparation thereof. Except insofar as any conventional carrier mediumis incompatible with the compounds of the invention, such as byproducing any undesirable biological effect or otherwise interacting ina deleterious manner with any other component(s) of the pharmaceuticalcomposition, its use is contemplated to be within the scope of thisinvention.

The pharmaceutical compositions of the invention can be manufactured bymethods well known in the art such as conventional granulating, mixing,dissolving, encapsulating, lyophilizing, or emulsifying processes, amongothers. Compositions may be produced in various forms, includinggranules, precipitates, or particulates, powders, including freezedried, rotary dried or spray dried powders, amorphous powders, tablets,capsules, syrup, suppositories, injections, emulsions, elixirs,suspensions or solutions. Formulations may optionally containstabilizers, pH modifiers, surfactants, bioavailability modifiers andcombinations of these.

Pharmaceutical formulations may be prepared as liquid suspensions orsolutions using a liquid, such as, but not limited to, an oil, water, analcohol, and combinations of these. Pharmaceutically suitablesurfactants, suspending agents, or emulsifying agents, may be added fororal or parenteral administration. Suspensions may include oils, such asbut not limited to, peanut oil, sesame oil, cottonseed oil, corn oil andolive oil. Suspension preparation may also contain esters of fatty acidssuch as ethyl oleate, isopropyl myristate, fatty acid glycerides andacetylated fatty acid glycerides. Suspension formulations may includealcohols, such as, but not limited to, ethanol, isopropyl alcohol,hexadecyl alcohol, glycerol and propylene glycol. Ethers, such as butnot limited to, poly(ethyleneglycol), petroleum hydrocarbons such asmineral oil and petrolatum; and water may also be used in suspensionformulations.

Pharmaceutically acceptable carriers that may be used in thesecompositions include, but are not limited to, ion exchangers, alumina,aluminum stearate, lecithin, serum proteins, such as human serumalbumin, buffer substances such as phosphates, glycine, sorbic acid,potassium sorbate, partial glyceride mixtures of saturated vegetablefatty acids, water, salts or electrolytes, such as protamine sulfate,disodium hydrogen phosphate, potassium hydrogen phosphate, sodiumchloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodiumcarboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

According to a preferred embodiment, the compositions of this inventionare formulated for pharmaceutical administration to a mammal, preferablya human being. Such pharmaceutical compositions of the present inventionmay be administered orally, parenterally, by inhalation spray,topically, rectally, nasally, buccally, vaginally or via an implantedreservoir. The term “parenteral” as used herein includes subcutaneous,intravenous, intramuscular, intra-articular, intra-synovial,intrasternal, intrathecal, intrahepatic, intralesional and intracranialinjection or infusion techniques. Preferably, the compositions areadministered orally, intravenously, or subcutaneously. The formulationsof the invention may be designed to be short-acting, fast-releasing, orlong-acting. Still further, compounds can be administered in a localrather than systemic means, such as administration (e.g., by injection)at a desired site.

Sterile injectable forms of the compositions of this invention may beaqueous or oleaginous suspension. These suspensions may be formulatedaccording to techniques known in the art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a non-toxicparenterally acceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose, any bland fixed oilmay be employed including synthetic mono- or di-glycerides. Fatty acids,such as oleic acid and its glyceride derivatives are useful in thepreparation of injectables, as are natural pharmaceutically-acceptableoils, such as olive oil or castor oil, especially in theirpolyoxyethylated versions. These oil solutions or suspensions may alsocontain a long-chain alcohol diluent or dispersant, such ascarboxymethyl cellulose or similar dispersing agents which are commonlyused in the formulation of pharmaceutically acceptable dosage formsincluding emulsions and suspensions. Other commonly used surfactants,such as Tweens, Spans and other emulsifying agents or bioavailabilityenhancers which are commonly used in the manufacture of pharmaceuticallyacceptable solid, liquid, or other dosage forms may also be used for thepurposes of formulation. Compounds may be formulated for parenteraladministration by injection such as by bolus injection or continuousinfusion. A unit dosage form for injection may be in ampoules or inmulti-dose containers.

The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers that are commonly used includelactose and corn starch. Lubricating agents, such as magnesium stearate,are also typically added. For oral administration in a capsule form,useful diluents include lactose and dried cornstarch. When aqueoussuspensions are required for oral use, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, the pharmaceutical compositions of this invention may beadministered in the form of suppositories for rectal administration.These may be prepared by mixing the agent with a suitable non-irritatingexcipient which is solid at room temperature but liquid at rectaltemperature and therefore will melt in the rectum to release the drug.Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract may be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used. For topicalapplications, the pharmaceutical compositions may be formulated in asuitable ointment containing the active component suspended or dissolvedin one or more carriers. Carriers for topical administration of thecompounds of this invention include, but are not limited to, mineraloil, liquid petrolatum, white petrolatum, propylene glycol,polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.Alternatively, the pharmaceutical compositions may be formulated in asuitable lotion or cream containing the active components suspended ordissolved in one or more pharmaceutically acceptable carriers. Suitablecarriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated asmicronized suspensions in isotonic, pH adjusted sterile saline, or,preferably, as solutions in isotonic, pH adjusted sterile saline, eitherwith our without a preservative such as benzylalkonium chloride.Alternatively, for ophthalmic uses, the pharmaceutical compositions maybe formulated in an ointment such as petrolatum.

The pharmaceutical compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

The compounds of this invention or pharmaceutical compositions thereofmay also be incorporated into compositions for coating implantablemedical devices, such as prostheses, artificial valves, vascular grafts,stents and catheters. Accordingly, the present invention, in anotheraspect, includes a composition for coating an implantable devicecomprising a compound of the present invention as described generallyabove, and in classes and subclasses herein, and a carrier suitable forcoating said implantable device. In still another aspect, the presentinvention includes an implantable device coated with a compositioncomprising a compound of the present invention as described generallyabove, and in classes and subclasses herein, and a carrier suitable forcoating said implantable device.

Vascular stents, for example, have been used to overcome restenosis(re-narrowing of the vessel wall after injury). However, patients usingstents or other implantable devices risk clot formation or plateletactivation. These unwanted effects may be prevented or mitigated bypre-coating the device with a pharmaceutically acceptable compositioncomprising a kinase inhibitor. Suitable coatings and the generalpreparation of coated implantable devices are described in U.S. Pat.Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings are typicallybiocompatible polymeric materials such as a hydrogel polymer,polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylacticacid, ethylene vinyl acetate, and mixtures thereof. The coatings mayoptionally be further covered by a suitable topcoat of fluorosilicone,polysaccarides, polyethylene glycol, phospholipids or combinationsthereof to impart controlled release characteristics in the composition.

The pharmaceutical compositions of the invention preferably areformulated for administration to a patient having, or at risk ofdeveloping or experiencing a recurrence of, an inflammatory, allergic orautoimmune disease, condition, or disorder. The term “patient”, as usedherein, means an animal, preferably a mammal, more preferably a human.Preferred pharmaceutical compositions of the invention are thoseformulated for oral, intravenous, or subcutaneous administration.However, any of the above dosage forms containing a therapeuticallyeffective amount of a compound of the invention are well within thebounds of routine experimentation and therefore, well within the scopeof the instant invention. In some embodiments, the pharmaceuticalcomposition of the invention may further comprise another therapeuticagent. In some embodiments, such other therapeutic agent is one that isnormally administered to patients with the disease or condition beingtreated.

As discussed above, compounds of the invention (including salts thereof)are useful as inhibitors of CCR2 activity. Several diseases anddisorders have been shown to be mediated at least in part by theactivation of CCR2. Thus, compounds of the invention are useful for thetreatment of (therapeutically or prophylactically) conditions mediatedby CCR2, including, but not limited to, inflammatory, allergic, orautoimmune diseases, conditions, or disorders. The disclosed compoundscan also be advantageously used for the treatment of diseases,conditions, or disorders mediated by esinophils, monocytes, Tlymphocytes and other immune system cells which express CCR2, includinginflammatory, allergic, or autoimmune diseases, conditions, or disordersmediated by these cells. When activation of CCR2 is implicated in aparticular disease, condition, or disorder, the disease, condition, ordisorder may also be referred to as “a CCR2-mediated disease, condition,or disorder” or disorder symptom. Accordingly, in another aspect, thepresent invention provides a method for the treatment of aninflammatory, allergic, or autoimmune disease, condition, or disorder isprovided comprising administering an effective amount of a compound or apharmaceutical composition to a subject in need thereof.

Examples of allergic conditions for which the disclosed compounds,pharmaceutical compositions and methods are particularly effectiveinclude asthma, atopic dermatitis, allergic rhinitis, systemicanaphylaxis or hypersensitivity responses, drug allergies (e.g., topenicillin, cephalosporins), insect sting allergies and dermatoses suchas dermatitis, eczema, atopic dermatitis, allergic contact dermatitisand urticaria.

Examples of diseases with an inflammatory component for which thedisclosed compounds, pharmaceutical composition and methods areeffective include rheumatoid arthritis, osteoarthritis, inflammatorybowel disease [e.g., such as ulcerative colitis, Crohn's disease,ileitis, Celiac disease, nontropical Sprue, enteritis, enteropathyassociated with seronegative arthropathies, microscopic or collagenouscolitis, eosinophilic gastroenteritis, or pouchitis resulting afterproctocolectomy, and ileoanal anastomosis] and disorders of the skin[e.g., psoriasis, erythema, pruritis, and acne].

Many autoimmune diseases also have an inflammatory component. Examplesinclude multiple sclerosis, systemic lupus erythematosus, myastheniagravis, juvenile onset diabetes, glomerulonephritis and othernephritides, autoimmune thyroiditis, Behcet's disease and graftrejection (including allograft rejection or graft-versus-host disease).The inflammatory component of these disorders is believed to bemediated, at least in part, by CCR2.

Diseases characterized by repurfusion have an inflammatory componentthat is believed to be mediated, at least in part by CCR2. Examplesinclude stroke, cardiac ischemia, and the like. The disclosed compoundsand pharmaceutical compositions also can be used to treat thesedisorders.

Other diseases and conditions with an inflammatory component believed tobe mediated by CCR2 include mastitis (mammary gland), vaginitis,cholecystitis, cholangitis or pericholangitis (bile duct and surroundingtissue of the liver), chronic bronchitis, chronic sinusitis, chronicinflanunatory diseases of the lung which result in interstitialfibrosis, such as interstitial lung diseases (ILD) (e.g., idiopathicpulmonary fibrosis, or ILD associated with rheumatoid arthritis, orother autoimmune conditions), cystic fibrosis, hypersensitivitypneumonitis, collagen diseases, neuropathic pain, and sarcoidosis.

Yet other diseases or conditions with inflammatory components which areamenable to treatment according to methods disclosed herein includevasculitis (e.g., necrotizing, cutaneous, and hypersensitivityvasculitis), spondyloarthropathies, scleroderma, atherosclerosis,restenosis and myositis (including polymyositis, dermatomyositis),pancreatitis and insulin-dependent diabetes mellitus.

Still other diseases or conditions which are amenable to treatmentaccording to methods disclosed herein include cancer, preferably breastcancer or multiple myeloma.

In some embodiments, the present invention provides a method fortreating rheumatoid arthritis, multiple sclerosis, scleroderma,atherosclerosis, neuropathic pain, type II diabetes, COPD (chronicobstructive pulmonary disorder), cystic fibrosis, hepatic fibrosis,inflammatory bowel disease, lung fibrosis, lupus, lupus nephritis,macular degeneration, cancer (including breast cancer and multiplemyeloma), acute and chronic organ transplant rejection, inflammatorypain, post MI remodeling, psoriasis, renal fibrosis, restenosis, stroke,uveitis, endometriosis, acute pancreatitis, peripheral vascular disease,sarcoidosis, or CIDP/Guillain-Barre disease comprising administering atherapeutically effective amount of a compound of formula I.

In still other embodiments, the present invention provides a method fortreating rheumatoid arthritis, multiple sclerosis, scleroderma,atherosclerosis, neuropathic pain, or type II diabetes comprisingadministering a therapeutically effective amount of a compound offormula I.

In yet other embodiments, the present invention provides a method fortreating rheumatoid arthritis or multiple sclerosis comprisingadministering a therapeutically effective amount of a compound offormula I.

As used herein, “treatment” or “treating” means partial alleviation,prevention, or cure of a disease, condition, or disorder as describedherein.

As used herein a “therapeutically effective amount” of the compound orpharmaceutical composition is that quantity required to achieve adesired therapeutic and/or prophylactic effect, such as an amount whichresults in the prevention of or a decrease in the symptoms associatedwith a disease, condition or disorder as described herein. In someembodiments, a therapeutically effective amount of a compound is thatamount which results in the inhibition of one or more of the processesmediated by the binding of a chemokine to a receptor such as CCR2 in asubject with a disease associated with aberrant leukocyte recruitmentand/or activation. Typical examples of such processes include leukocytemigration, integrin activation, transient increases in the concentrationof intracellular free calcium and granule release of proinflammatorymediators.

Compounds and pharmaceutical compositions, according to the method ofthe present invention, may be administered using any amount and anyroute of administration effective for treating a disease, condition, ordisorder as described herein. The skilled artisan will be able todetermine appropriate dosages depending on these and other factors. An“effective amount” typically ranges between about 0.01 mg/kg/day toabout 100 mg/kg/day, preferably between about 0.5 mg/kg/day to about 50mg/kg/day. In other embodiments, an effective amount typically rangesbetween about 1 mg/kg/day to about 25 mg/kg/day.

The exact amount required will vary from subject to subject, dependingon the species, age, and general condition of the subject, the severityof the infection, the particular agent, its mode of administration, andthe like. The compounds of the invention are preferably formulated indosage unit form for ease of administration and uniformity of dosage.The expression “dosage unit form” as used herein refers to a physicallydiscrete unit of agent appropriate for the patient to be treated. Itwill be understood, however, that the total daily usage of the compoundsand compositions of the present invention will be decided by theattending physician within the scope of sound medical judgment. Thespecific effective dose level for any particular patient or organismwill depend upon a variety of factors including the disorder beingtreated and the severity of the disorder; the activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts.

The term “subject”, as used herein, is preferably a bird or mammal, suchas a human (Homo sapiens), but can also be an animal in need ofveterinary treatment, e.g., domestic animals (e.g., dogs, cats, and thelike), farm animals (e.g., cows, sheep, fowl, pigs, horses, and thelike) and laboratory animals (e.g., rats, mice, guinea pigs, and thelike).

It will also be appreciated that the compounds and pharmaceuticalcompositions of the present invention can be employed in combinationtherapies, that is, the compounds and pharmaceutical compositions can beadministered concurrently with, prior to, or subsequent to, one or moreother desired therapeutics or medical procedures. The particularcombination of therapies (therapeutics or procedures) to employ in acombination regimen will take into account compatibility of the desiredtherapeutics and/or procedures and the desired therapeutic effect to beachieved. It will also be appreciated that the therapies employed mayachieve a desired effect for the same disorder (for example, aninventive compound may be administered concurrently with another agentused to treat the same disorder), or they may achieve different effects(e.g., control of any adverse effects). As used herein, additionaltherapeutic agents which are normally administered to treat or prevent aparticular disease, or condition, are known as “appropriate for thedisease, or condition, being treated”. Exemplary additional therapeuticagents for use with an antagonist of chemokine receptor functioninclude, but are not limited to theophylline, β-adrenergicbronchodilators, corticosteroids, antihistamines, antiallergic agents,immunosuppressive agents (e.g., cyclosporin A, FK-506, prednisone,methylprednisolone), hormones (e.g., adrenocorticotropic hormone(ACTH)), cytokines (e.g., interferons (e.g., IFNβ-1α, IFNβ-1β)) and thelike.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

EXAMPLES

Although certain exemplary embodiments are depicted and describedherein, it will be appreciated that compounds of the invention can beprepared using appropriate starting materials according to the methodsdescribed generally herein and/or by methods generally available to oneof ordinary skill in the art. Additional embodiments are exemplified inmore detail herein. Exemplary compounds of formula I are depicted inTable 1 below and described in the examples below.

General. All reactions involving air-sensitive reagents were performedunder a nitrogen atmosphere. Reagents were used as received fromcommercial suppliers unless otherwise noted. ¹H NMR data were recordedusing the Bruker UltraShield 300 MHz/54 mm instrument equipped withBruker B-ACS60 Auto Sampler or the Varian 300 MHz instrument.Intermediates and final compounds were purified by flash chromatographyusing one of the following instruments: 1. Biotage 4-channel Quad UVFlash Collector equipped with a Quad 1 Pump Module and the Quad 12/25Cartridge module. 2. Biotage 12-channel Quad UV Flash Collector equippedwith a Quad 3 Pump Module and a Quad 3 Cartridge module. 3. ISCOcombi-flash chromatography instrument. LC/MS spectra were obtained usinga MicroMass Platform LC (Phenomenx C18 column, 5 micron, 50×4.6 mm)equipped with a Gilson 215 Liquid Handler. Standard LC/MS conditions areas follows. LC-MS data were acquired using the “Ammoniumacetate-standard” method unless otherwise noted.

Ammonium Acetate-Standard Conditions:

% A (Water) 95.0 % B (Acetonitrile) 5.0 % Ammonium acetate 0.1 Flow(ml/min) 2.500 Stop Time (mins) 3.8 Min Pressure (bar) 0 Max Pressure(bar) 400 Oven Temperature Left (° C.) 10.0 Oven Temperature Right (°C.) 10.0 HP1100 LC Pump Gradient Timetable The gradient Timetablecontains 4 entries which are: Time A % B % C % D % Flow Pressure 0.0095.0 5.0 0.0 0.0 2.500 400 2.00 0.0 100.0 0.0 0.0 2.500 400 3.00 0.0100.0 0.0 0.0 2.500 400 3.05 95.0 5.0 0.0 0.0 2.000 400

Benzyl(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]-1,3′-bipyrrolidine-1′-carboxylate(1)

To a solution ofN-{2-oxo-2-[(3R)-pyrrolidin-3-ylamino]ethyl}-3-(trifluoromethyl)benzamide(500 mg, 1.59 mmol; prepared according to WO2004/050024A2) in methanol(5 mL) at room temperature was added benzyl3-oxopyrrolidine-1-carboxylate (434 mg, 1.98 mmol) followed by sodiumtriacetoxyborohydride (470 mg, 2.22 mmol); the reaction mixture wasstirred for 16 hours. To the mixture was added NaHCO₃ (sat. aq., 10 mL)and dichloromethane (10 mL). The organic layer was separated and theaqueous layer was washed with an addition portion of dichloromethane (10mL). The organic layers were combined, dried over Na₂SO₄, filtered andconcentrated. The resulting crude product was subjected to flashchromatography (15% MeOH, 1% NH₄OH in EtOAc) to afford, as a mixture ofdiastereomers, benzyl(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]-1,3′-bipyrrolidine-1′-carboxylate(906 mg, 88%) as a white solid. ¹H-NMR (CDCl₃) δ: 1.30-1.44 (m, 2H),1.50-1.68 (m, 2H), 1.80-2.00 (m, 2H), 2.10-3.29 (m, 1H), 2.30-2.43 (m,1H), 2.55-23.05 (m, 3H), 3.15-3.28 (m, 1H), 3.58-4.20 (m, 3H), 4.30-4.50(m, 1H), 5.09 (s, 2H), 6.70-6.87 (m, 1H), 7.20-7.50 (m, 6H), 7.52 (t,J=8.7 Hz, 1H), 7.72 (d, J=7.2 Hz, 1H), 7.99 (d, J=7.2 Hz, 1H), 8.09 (s,1H). MS m/z: 519 (M+1)

N-(2-{[(3R)-1′-(4-methoxyphenyl)-5′-oxo-1,3′-bipyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide(2)

To a solution of N-allyl-4-methoxyaniline (1.00 g, 6.13 mmol) inmethylene chloride (20 mL) was added K₂CO₃ (2.12 mg, 15.3 mmol) andacryloyl chloride (548 μL, 6.74 mmol) at 0° C. After 15 min., thereaction was quenched with NaHCO₃ (5 mL, sat. aq.) and the organic layerwas isolated, concentrated and subjected to flash chromatography(Hexanes:EtOAc 4:1) to yield N-allyl-N-(4-methoxyphenyl)acrylamide (1.29mg, 97%).

To a solution of N-allyl-N-(4-methoxyphenyl)acrylamide (150 mg, 0.69mmol) in degassed methylene chloride (400 mL) was added Grubbs catalyst(58 mg, 0.069 mmol) and the mixture was heated to 40° C. overnight. Allvolatiles were removed and the resulting material was subjected to flashchromatography (Hexanes:EtOAc 1:1) to yield1-(4-methoxyphenyl)-1,5-dihydro-2H-pyrrol-2-one (110 mg, 86%).

A slurry of water (20 μL, 0.10 mmol),1-(4-methoxyphenyl)-1,5-dihydro-2H-pyrrol-2-one (200 mg, 1.06 mmol) andN-{2-oxo-2-[(3R)-pyrrolidin-3-ylamino]ethyl}-3-(trifluoromethyl)benzamide(666 mg, 2.12 mmol) was heated to 90° C. overnight. The crude mixturewas subjected to flash chromatography (1% NH₄OH, 15% MeOH, EtOAc) toafford, as a mixture of diastereomers,N-(2-{[(3R)-1′-(4-methoxyphenyl)-5′-oxo-1,3′-bipyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamideas a white solid (115 mg, 21%). ¹H-NMR (CDCl₃) δ: 1.50-1.82 (m, 1H),1.83-2.00 (m, 1H), 2.18-2.40 (m, 1H), 2.40-2.58 (m, 1H), 2.56-2.81 (m,3H), 2.83-3.00 (m, 2H), 3.29-3.33 (m, 2H), 3.60-3.71 (m, 2H), 3.79 (s,3H), 4.04-4.20 (m, 2H), 4.38-4.47 (m, 1H), 6.94 (m, 2H), 7.19-7.30 (m,2H), 7.69-7.80 (m, 2H), 7.99 (d, J=7.8 Hz, 1H), 8.18 (s, 1H). MS m/z:505 (M+1).

Benzyl4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]-1,3′-bipyrrolidin-1′-yl}benzoate(3)

In a round-bottom flask, a slurry of benzyl(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]-1,3′-bipyrrolidine-1′-carboxylate(0.765 g, 1.48 mmol) and Palladium (10%) on Carbon (0.200 g) in methanol(10 mL) was purged with hydrogen gas for 2 min.; the reaction was thensubjected to 1 atm of hydrogen gas for 3 h. The flask was purged withArgon, then the mixture was filtered and concentrated to affordN-{2-[(3R)-1,3′-bipyrrolidin-3-ylamino]-2-oxoethyl}-3-(trifluoromethyl)benzamide(0.551 g, 97%) as an off-white solid. ¹H-NMR (CDCl₃) δ: 1.32-1.53 (m,2H), 1.52-2.04 (m, 6H), 2.15-2.40 (m, 2H), 2.40-2.70 (m, 3H), 2.80-3.00(m, 3H), 4.00-4.20 (m, 2H), 4.42 (bs, 1H), 6.77 (m, 1H), 7.40-7.55 (m,1H), 7.53 (t, J=7.8 Hz, 1H), 7.73 (d, J=7.2 Hz, 1H), 7.98 (d, J=7.5 Hz,1H), 8.08 (s, 1H). MS m/z: 399 (M+1).

To a solution ofN-{2-[(3R)-1,3′-bipyrrolidin-3-ylamino]-2-oxoethyl}-3-(trifluoromethyl)benzamide(525 mg, 1.36 mmol) in DMSO (3 mL) was added K₂CO₃ (940 mg, 6.8 mmol)followed by benzyl 4-fluorobenzoate (786 mg, 3.41 mmol). The mixture washeated to 120° C. for 16 hours. The crude mixture was subjected tocolumn chromatography (15% MeOH, 1% NH₄OH in EtOAc) to afford, as amixture of diastereomers,N-{2-[(3R)-1,3′-bipyrrolidin-3-ylamino]-2-oxoethyl}-3-(trifluoromethyl)benzamide(355 mg, 44%) as a white solid. ¹H-NMR (MeOD) δ: 1.70-1.80 (m, 1H),1.92-2.04 (m, 1H), 2.20-2.36 (m, 2H), 2.56-2.70 (m, 2H), 2.84-2.96 (m,2H), 2.96-3.09 (m, 1H), 3.20-3.42 (m, 4H), 3.46-3.62 (m, 2H), 4.03 (s,2H), 4.37-4.50 (m, 1H), 5.29 (s, 2H), 6.57 (d, J=9.0 Hz, 2H), 7.27-7.46(m, 5H), 7.68 (t, J=6.9 Hz, 1H), 7.82-7.90 (m, 3H), 8.14 (d, J=8.1 Hz,1H), 8.22 (s, 1H). MS m/z: 595 (M+1)

N,N-diethyl-4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]-1,3′-bipyrrolidin-1′-yl}benzamide(4)

In a round-bottom flask, a solution of benzyl4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]-1,3′-bipyrrolidin-1′-yl}benzoate(258 mg, 0.43 mmol) in methanol (400 μL) and Palladium (10%) on Carbon(50 mg) was purged with hydrogen gas for two minutes; the reaction wasthen subjected to 1 atmosphere of hydrogen gas for two hours. The flaskwas purged with Argon, then the mixture was filtered and concentrated toafford4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]-1,3′-bipyrrolidin-1′-yl}benzoicacid (197 mg, 91%) as an off-white solid.

To a solution of4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]-1,3′-bipyrrolidin-1′-yl}benzoicacid (35 mg, 0.069 mmol), HATU (0.032 g, 0.086 mmol),N,N-diisopropylethylamine (30.2 μL, 0.173 mmol), 1-Hydroxybenzotriazole(11.7 mg, 0.0867 mmol) in DMF (3.0 mL) was added diethylame (8.25 μL,0.079 mmol). The reaction mixture was allowed to stir at roomtemperature overnight. To the mixture was added NaHCO₃ (sat. aq., 10 mL)and dichloromethane (10 mL). The organic layer was separated and theaqueous layer was washed with an addition portion of dichloromethane (10mL). The organic layers were combined, dried over Na₂SO₄, filtered andconcentrated. The resulting crude product was subjected to flashchromatography (15% MeOH, 1% NH₄OH in EtOAc) to afford, as a mixture ofdiastereomers,N,N-diethyl-4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]-1,3′-bipyrrolidin-1′-yl}benzamide(32 mg, 82%) as a white solid. ¹H-NMR (MeOD) δ: 1.19 (t, J=6.6 Hz, 6H),1.66-1.80 (m, 1H), 1.90-2.05 (m, 1H), 2.18-2.40 (m, 2H), 2.50-2.70 (m,2H), 2.80-3.06 (m, 4H), 3.15-3.40 (m, 4H), 3.38-3.60 (m, 5H), 4.03 (s,2H), 4.37-4.50 (m, 1H), 6.58 (d, J=8.4 Hz, 2H), 7.26 (d, J=8.1 Hz, 2H),7.69 (t, J=7.2 Hz, 1H), 7.86 (d, J=7.2 Hz, 1H), 8.14 (d, J=7.5 Hz, 1H),8.22 (s, 1H). MS m/z: 560 (M+1)

N-[2-({(3R)-1′-[4-(morpholin-4-ylcarbonyl)phenyl]-1,3′-bipyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide(5)

The title compound was synthesized in similar fashion toN,N-diethyl-4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]-1,3′-bipyrrolidin-1′-yl}benzamide,substituting morpholine for diethylamine, and was isolated, as a mixtureof diastereomers, as a white solid. ¹H-NMR (MeOD) δ: 1.55-1.6.5 (m, 1H),1.67-1.82 (m, 1H), 1.90-2.06 (m, 1H), 2.20-2.36 (m, 2H), 2.56-2.68 (m,2H), 2.84-2.95 (m, 2H), 2.96-3.06 (m, 1H), 3.18-3.40 (m, 2H), 3.42-3.60(m, 2H), 3.60-3.74 (m, 10H), 4.03 (s, 2H), 4.39-4.50 (m, 1H), 6.59 (d,J=8.7 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 7.69 (t, J=8.1 Hz, 1H), 7.86 (d,J=7.5 Hz, 1H), 8.22 (s, 1H). MS m/z: 574 (M+1)

N-(2-oxo-2-{[(3R)-1-(tetrahydro-3-thienyl)pyrrolidin-3-yl]amino}ethyl)-3-(trifluoromethyl)benzamide(6)

The title compound was synthesized in similar fashion to benzyl(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]-1,3′-bipyrrolidine-1′-carboxylate,whereby dihydrothiophen-3(2H)-one was substituted for benzyl3-oxopyrrolidine-1-carboxylate, and was isolated, as a mixture ofdiastereomers, as a white solid. ¹H-NMR (CDCl₃) δ: 1.55-1.66 (m, 1H),1.71-1.81 (m, 1H), 2.03-2.14 (m, 1H), 2.15-2.26 (m, 1H), 2.33-2.39 (m,1H), 2.52-2.58 (m, 1H), 2.63-2.73 (m, 3H), 2.74-2.81 (m, 4H), 4.07 (d,J=4.8 Hz, 2H), 4.36-4.38 (m, 1H), 7.04 (d, J=7.8 Hz, 1H), 7.46 (t, J=7.9Hz, 1H), 7.67 (d, J=7.5 Hz, 1H), 7.81 (t, J=4.9 Hz, 1H), 7.93 (d, J=8.4Hz, 1H), 8.03 (s, 1H). MS m/z: 402 (M+1)

Methyl4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]-1,3′-bipyrrolidin-1′-yl}benzoate(7)

A slurry ofN-{2-[(3R)-1,3′-bipyrrolidin-3-ylamino]-2-oxoethyl}-3-(trifluoromethyl)benzamide(50 mg, 0.13 mmol), methyl 4-bromobenzoate (35 mg, 0.16 mmol), Pd₂(dba)₃(12 mg, 0.013 mmol), cesium carbonate (64 mg, 0.19 mmol) and R-BINAP (8mg, 0.013 mmol) in toluene was heated at 100° C. overnight. To themixture was added NaHCO₃ (sat. aq., 10 mL) and dichloromethane (10 mL).The organic layer was separated and the aqueous layer was washed with anaddition portion of dichloromethane (10 mL). The organic layers werecombined, dried over Na₂SO₄, filtered and concentrated. The resultingcrude product was subjected to flash chromatography (15% MeOH, 1% NH₄OHin EtOAc) to afford, as a mixture of diastereomers, methyl4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]-1,3′-bipyrrolidin-1′-yl}benzoate(20 mg, 30%) as a white solid. ¹H-NMR (CDCl₃) δ: 1.60-1.76 (m, 1H),1.86-2.04 (m, 1H), 2.08-2.25 (m, 1H), 2.20-2.44 (m, 2H), 2.60-2.78 (m,2H), 2.84-3.00 (m, 2H), 3.18 (q, J=8.7 Hz, 1H), 3.32 (q, J=7.5 Hz, 1H),3.40-3.54 (m, 2H), 3.82 (s, 3H), 4.10 (m, 2H), 4.40-4.56 (m, 1H), 6.44(d, J=8.7 Hz, 2H), 6.54 (d, J=2.4 Hz, 1H), 7.20-7.35 (m, 1H), 7.54 (t,J=7.8 Hz, 1H), 7.74 (d, J=8.1 Hz, 1H), 7.87 (d, J=8.4 Hz, 2H), 7.97 (d,J=7.8 Hz, 1H), 8.07 (s, 1H). MS m/z: 519 (M+1)

Compounds 8-143 can also be prepared by the methods described herein.Those skilled in the art will be able to recognize, or be able toascertain, using no more than routine experimentation, many equivalentsto the specific embodiments of the invention described herein.

TABLE 1

 1

 2

 3

 4

 5

 6

 7

 8

 9

 10

 11

 12

 13

 14

 15

 16

 17

 18

 19

 20

 21

 22

 23

 24

 25

 26

 27

 28

 29

 30

 31

 32

 33

 34

 35

 36

 37

 38

 39

 40

 41

 42

 43

 44

 45

 46

 47

 48

 49

 50

 51

 52

 53

 54

 55

 56

 57

 58

 59

 60

 61

 62

 63

 64

 65

 66

 67

 68

 69

 70

 71

 72

 73

 74

 75

 76

 77

 78

 79

 80

 81

 82

 83

 84

 85

 86

 87

 88

 89

 90

 91

 92

 93

 94

 95

 96

 97

 98

 99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

Biological Testing

THP-1 FLIPR Assay

The primary screening assay is a FLIPR (Fluorometric Imaging PlateReader) assay using THP-1 cells (ATCC, Catalog No. TIB 202), a monocyticderived cell line that endogenously expresses CCR2.

The cells were resuspended at 1×10⁶ cells/ml in dye loading media(growth media (RPMI+10% FBS (Fetal Bovine serum)+5.5×10⁻⁵M2-mercaptoethanol)+10 mM HEPES(N-2-hydroxyethylpiperazine-N′-2-ethane-sulfonic acid)+2.5 mMprobenecid+fluo-3 (1:250)). The cells were incubated for 1 hour at 37°C. and then washed in FLIPR wash buffer (100 mL 10×BBSS (Hanks BufferedSaline Solution) (w/Ca++/Mg++)+20 mL 1M HEPES+1 g BSA+10 mL 250 mMprobenecid+water (to make 1 L)) and plated at 50,000 cells/well inblack/clear 384 well plates. The plates were transferred to FLIPR wherethe ability of different concentrations of compounds to inhibit MCP-1induced calcium flux was assessed. Inhibition of the CCR2 response wasreflected by a decrease of the fluorescence signal relative to thepositive controls (MCP-1 alone).

THP-1 Whole Cell Radioligand Binding Assay

The cells were washed with PBS (phosphate buffered saline) andresuspended in binding buffer (10 mM HEPES pH 7.2, 1×HBSS (w/Ca²⁺, Mg²⁺)0.5% BSA, 0.02% Na-azide) at 4×10⁶ cells/ml (for 200,000 cells/well).Cells were incubated with 0.1 to 0.2 nM [¹²⁵I]-labeled MIP-1α with orwithout unlabeled competitor (MIP-1α) or various concentrations ofcompounds for 60 minutes at room temperature. The assay was terminatedby vacuum filtration through glass fiber filters (GF/B, Packard) whichwere presoaked in 0.3% polyethyleneimine. The filters were washed withwash buffer (10 mM HEPES, pH 7.2, 1 mM CaCl₂, 5 mM MgCl₂ 0.5M NaCl),dried and the amount of bound radioactivity was determined byscintillation counting.

Compounds of the invention have been shown to inhibit CCR2, preferablyat a concentration less than 100 nM.

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein: Y is -Y₁-Y₂-,wherein: Y₁ is —SO₂N(R′)—, —C(O)N(R′)—; —C(O)N(R′)C(O)—, —N(R′)SO₂—,—N(R′)SO₂N(R′)—, —N(R′)C(O)—, —NR′C(O)N(R′)—, or —N(R′)C(O)O—; and Y₂ isabsent or is an optionally substituted C₁₋₆ alkylene chain, wherein oneor two methylene units of Y₂ are optionally and independentlyinterrupted by —O—, —S—, —N(R′)—, —C(O)—, —OC(O)—, —C(O)O—, —S(O)—,—S(O)₂—, —C(O)N(R′)—, —N(R′)C(O)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—,—OC(O)N(R′)—, —N(R′)S(O)₂—, or —S(O)₂N(R′)—, or wherein Y₂, or a portionthereof, is an optionally substituted ring selected from 3-6-memberedcycloaliphatic, 3-6-membered heterocyclyl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-memberedaryl, or 5-6-membered heteroaryl having 1-3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur; each R′ is independentlyhydrogen or optionally substituted C₁₋₆aliphatic; R¹ is an optionallysubstituted group selected from 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; ring A is substituted at one or more carbon atomswith m independent occurrences of R²; m is 0-6; each occurrence of R² isindependently halogen, ═O, ═S, —CN, -R^(2b), N(R^(2a))₂, —OR², SR^(2b),S(O)₂R^(2b), —C(O)R^(2a), —C(O)OR^(2a), —C(O)N(R^(2a))₂,—S(O)₂N(R^(2a))₂, —OC(O)N(R^(2a))₂, —N(R′)C(O)R^(2a), —N(R′)SO₂R^(2b),—N(R′)C(O)OR^(2a), —N(R′)C(O)N(R^(2a))₂, or —N(R′)SO₂N(R^(2a))₂, or twooccurences of R^(2a) or R^(2b) are optionally taken together with theirintervening atom(s) to form an optionally substituted spiro, fused, orbridged ring selected from 6-membered aryl, 3-6-membered cycloaliphatic,3-7-membered heterocyclyl having 1-3 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3heteroatoms independently selected from nitrogen, oxygen, or sulfur, ortwo occurrences of R^(2a), taken together with the nitrogen atom towhich they are bound, form an optionally substituted 3-7-memberedheterocyclyl ring having 1-3 additional heteroatoms selected fromnitrogen, oxygen, or sulfur; each occurrence of R^(2a) is independentlyhydrogen or an optionally substituted group selected from C₁₋₆aliphatic,3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur,6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; each occurrenceof R^(2b) is independently an optionally substituted group selected fromC₁₋₆aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur;ring B is substituted with r independent occurrences of -R³; r is 0-6;each occurrence of R³ is independently -R^(3a), -T₁-R^(3d), or—V₁-T₁-R^(3d), wherein: each occurrence of -R^(3a) is independentlyhalogen, —CN, —NO₂, -R^(3c), —N(R^(3b))₂, —OR^(3b), SR^(3c),—S(O)₂R^(3c), —C(O)R^(3b), —C(O)OR^(3b), —C(O)N(R^(3b))₂,—S(O)₂N(R^(3b))₂, —OC(O)N(R^(3b))₂, —N(R′)C(O)R^(3b), —N(R′)SO₂R^(3c),—N(R′)C(O)OR^(3b), —N(R′)C(O)N(R^(3b))₂, or —N(R′)SO₂N(R^(3b))₂, or twooccurences of R^(3b) or R^(3c) are optionally taken together with theirintervening atom(s) to form an optionally substituted spiro, fused, orbridged ring selected from 6-membered aryl, 3-6-membered cycloaliphatic,3-7-membered heterocyclyl having 1-3 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3heteroatoms independently selected from nitrogen, oxygen, or sulfur, ortwo occurrences of R^(3b), taken together with the nitrogen atom towhich they are bound, form an optionally substituted 3-7-memberedheterocyclyl ring having 1-3 additional heteroatoms selected fromnitrogen, oxygen, or sulfur; each occurrence of R^(3b) is independentlyhydrogen or an optionally substituted group selected from C₁₋₆aliphatic,3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur,6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; each occurrenceof R^(3c) is independently an optionally substituted group selected fromC₁₋₆aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur;each occurrence of R^(3d) is independently an optionally substitutedgroup selected from 3-10-membered cycloaliphatic, 3-10-memberedheterocyclyl having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; each occurrence of V₁ is independently —C(R′)═C(R′)—,—C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R′)—,—S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO₂—, —N(R′)C(O)O—,—NR′C(O)N(R′)—, —N(R′)SO₂N(R′)—, —OC(O)—, or —C(O)N(R′)—O—; eachoccurrence of T₁ is independently C₁₋₆ alkylene chain optionallysubstituted with R^(3a), wherein the alkylene chain optionally isinterrupted by —C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O)₂—,—C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—,—N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)SO₂N(R′)—, —OC(O)—, or—C(O)N(R′)—O— or wherein T¹ or a portion thereof optionally forms partof an optionally substituted 3-7 membered cycloaliphatic or heterocyclylring; X is —O—, —S—, —SO₂—, or —N(W—R⁴)—; W is absent or is a groupselected from —W₁-L₂-W₂-, wherein W₁ and W₂ are each independentlyabsent or are an optionally substituted C₁₋₃alkylene chain, and L₂ isabsent or is a group selected from —N(R)—, —O—, —S—, —S(O)—, —S(O)₂—,—C(O)—, —C(O)O—, —C(O)N(R)—, —S(O)₂N(R)—, —OC(O)N(R)—, —N(R)C(O)—,—N(R)SO₂—, —N(R)C(O)O—, —N(R)C(O)N(R)—, —N(R)SO₂N(R)—, —OC(O)—, or—C(O)N(R)—O—, wherein R is hydrogen or C₁-C₄alkyl, provided that if WIis absent then L₂ is selected from —C(O)—, —C(O)O—, —C(O)O—, —S(O)—,—S(O)₂—, —C(O)N(R)—, or —S(O)₂N(R)— R⁴ is an optionally substitutedmonocyclic or bicyclic ring selected from 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur, provided that the compound is other than: a)1-Pyrrolidinecarboxamide,3-[6-(4-chlorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl]-N-methyl-N-[(3S)-1-(tetrahydro-2-oxo-3-furanyl)-3-pyrrolidinyl]-,(3S)—; pcomp also b) Pentitol,1,4-anhydro-2,3,5-trideoxy-3-[(3R)-3-[methyl[[(3S)-3-[methyl[[(4-phenoxyphenyl)amino]carbonyl]amino]-1-pyrrolidinyl]carbonyl]amino]-1-pyrrolidinyl]-pcomp also c) 1-Pyrrolidinecarboxamide,N-methyl-3-[methyl[[4′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl]amino]-N-[(3R)-1′-(phenylmethyl)[1,3′-bipyrrolidin]-3-yl]-,(3S)— pcomp d) Pentitol,1,4-anhydro-2,3,5-trideoxy-3-[(3R)-3-[methyl[[(3S)-3-[methyl[[4′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl]amino]-1-pyrrolidinyl]carbonyl]amino]-1-pyrrolidinyl]-pcomp e) [1,3′-Bipyrrolidine]-1′-carboxylic acid,3-[(hydroxyamino)carbonyl]-4-[[4-[(2-methyl-4-quinolinyl)methoxy]benzoyl]amino]-,1,1-dimethylethyl ester, (3R,4R)-rel- pcomp and inflamm; and f)[1,3′-Bipyrrolidine]-3-carboxamide,N-hydroxy-4-[[4-[(2-methyl-4-quinolinyl)methoxy]benzoyl]amino]-,(3R,4R)-rel- pcomp and inflamm
 2. The compound of claim 1, wherein thecompound has the structure of formula I-A-I or I-A-ii:


3. The compound of claim 2, wherein r is 0, 1, or
 2. 4. The compound ofclaim 3, wherein r is 1 and the compound has the structure of formulaI-B:


5. The compound of claim 3, wherein r is 2 and the compound has thestructure of I-B-i:

wherein the two occurrences of R³, taken together, form an optionallysubstituted 3-6-membered spiro carbocyclic or heterocyclic ring.
 6. Thecompound of claim 4 or 5, wherein R¹ is an optionally substituted arylgroup.
 7. The compound of claim 5, wherein R¹ is an optionallysubstituted phenyl group.
 8. The compound of claim 4 or 5, wherein R¹ isan optionally substituted 5-8-membered monocyclic or 7-10-memberedbicyclic heterocyclyl or heteroaryl ring having 1-4 heteroatomsindependently selected from N, O, or S.
 9. The compound of claim 8,wherein R¹ is an optionally substituted group selected from:


10. The compound of claim 8, wherein R¹ is an optionally substitutedgroup selected from:


11. The compound of claims 4 or 5, wherein: R¹ is an optionallysubstituted aryl group or R¹ is an optionally substituted 5-8-memberedmonocyclic or 7-10-membered bicyclic heterocyclyl or heteroaryl ringhaving 1-4 heteroatoms independently selected from N, O, or S, and R¹ isoptionally substituted with 1-3 occurrences of R^(1a), wherein eachoccurrence of R^(1a) is independently halogen, ═O, ═S, —CN, —NO₂,-R^(1c), —N(R^(1b))₂, —OR^(1b), —SR^(1c), —S(O)₂R^(1c), —C(O)R^(1b),—C(O)OR^(1b), —C(O)N(R^(1b))₂, —S(O)₂N(R^(1b))₂, —OC(O)N(R^(1b))₂,—N(R′)C(O)R^(1b), —N(R′)SO₂R^(1c), N(R′)C(O)OR^(1b),N(R′)C(O)N(R^(1b))₂, or —N(R′)SO₂N(R^(1b))₂, or two occurences of R^(1b)or R^(1c) are optionally taken together with their intervening atom(s)to form an optionally substituted spiro, fused, or bridged ring selectedfrom 6-membered aryl, 3-6-membered cycloaliphatic, 3-7-memberedheterocyclyl having 1-3 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3heteroatoms independently selected from nitrogen, oxygen, or sulfur, ortwo occurrences of R^(1b), taken together with the nitrogen atom towhich they are bound, form an optionally substituted 3-7-memberedheterocyclyl ring having 1-3 additional heteroatoms selected fromnitrogen, oxygen, or sulfur, wherein each occurrence of R^(1b) isindependently hydrogen or an optionally substituted group selected fromC₁₋₆aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur; andeach occurrence of R^(1c) is independently an optionally substitutedgroup selected from C₁₋₆aliphatic, 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur.
 12. The compound of claim 11, wherein each occurrenceof R^(1a) is independently ═O, halogen, -R^(1c), —N(R^(1b))₂, —OR^(1b),or SR^(1c).
 13. The compound of claim 11, wherein each occurrence ofR^(1a) is independently C₁₋₄-fluoroalkyl, —O(C₁₋₄-fluoroalkyl), or—S(C₁₋₄-fluoroalkyl).
 14. The compound of claim 4 or 5, wherein Y₁ is—SO₂N(R′)—, —C(O)NR′—, or —N(R′)S(O)₂—.
 15. The compound of claim 4 or5, wherein Y₁ is —N(R′)C(O)—.
 16. The compound of claim 4 or 5, whereinY₁ is selected from:


17. The compound of claim 4 or 5, wherein X is O.
 18. The compound ofclaim 4 or 5, wherein X is —N(W—R⁴).
 19. The compound of claim 4 or 5,wherein X is O, m is 1, and R² is an optionally substituted groupselected from a monocyclic 3-8-membered heterocyclyl having 1-2heteroatoms independently selected from nitrogen, oxygen, or sulfur, abicyclic 7-10-membered heterocyclyl having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, a monocyclic 5-6-memberedheteroaryl having 1-3 heteroatoms independently selected from nitrogen,oxygen, or sulfur, or a 7-10-membered heteroaryl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.
 20. Thecompound of claim 4 or 5, wherein X is —N(W—R⁴) and R⁴ is an optionallysubstituted group selected from a monocyclic 3-8-membered heterocyclylhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, orsulfur, a bicyclic 7-10-membered heterocyclyl having 1-2 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, a monocyclic5-6-membered heteroaryl having 1-3 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, or a 7-10-membered heteroaryl having1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.21. The compound of claim 4 or 5, wherein X is —N(W—R⁴), W is absent andR⁴ is optionally substituted phenyl.
 22. The compound of claim 4 or 5,wherein: X is —N(W—R⁴) and R⁴ is an optionally substituted groupselected from a monocyclic 3-8-membered heterocyclyl having 1-2heteroatoms independently selected from nitrogen, oxygen, or sulfur, abicyclic 7-10-membered heterocyclyl having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, a monocyclic 5-6-memberedheteroaryl having 1-3 heteroatoms independently selected from nitrogen,oxygen, or sulfur, or a 7-10-membered heteroaryl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or X is—N(W—R⁴), W is absent and R⁴ is optionally substituted phenyl, wherein:R⁴ is optionally substituted with 1-3 occurrences of R^(4a) and eachoccurrence of R^(4a) is independently -R^(4b), -T₁-R^(4e), or—V₁-T₁-R^(4e), wherein each occurrence of -R^(4b) is independentlyhalogen, —CN, —NO₂, -R^(4d), —N(R^(4c))₂, —OR^(4c), SR^(4d),S(O)₂R^(4d), —C(O)R^(4c), —C(O)OR^(4c), —C(O)N(R^(4c))₂,—S(O)₂N(R^(4c))₂, —OC(O)N(R^(4c))₂, —N(R′)C(O)R^(4c), —N(R′)SO₂R^(4d),—N(R′)C(O)OR^(e), —N(R′)C(O)N(R^(4c))₂, or —N(R′)SO₂N(R^(4c))₂, or twooccurences of R^(4b), R^(4c) or R^(d) are optionally taken together withtheir intervening atom(s) to form an optionally substituted spiro,fused, or bridged ring selected from 6-membered aryl, 3-6-memberedcycloaliphatic, 3-7-membered heterocyclyl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or 5-6-memberedheteroaryl having 1-3 heteroatoms independently selected from nitrogen,oxygen, or sulfur or two occurrences of R^(4c), taken together with thenitrogen atom to which they are bound, form an optionally substituted3-7-membered heterocyclyl ring having 1-3 additional heteroatomsselected from nitrogen, oxygen, or sulfur; each occurrence of R^(4c) isindependently hydrogen or an optionally substituted group selected fromC₁₋₆aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur;each occurrence of R^(4d) is independently an optionally substitutedgroup selected from C₁₋₆aliphatic, 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; each occurrence of R^(4e) is independently anoptionally substituted group selected from 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; each occurrence of V₁ is independently —C(R′)═C(R′)—,—C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R′)—,—S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO₂—, —N(R′)C(O)O—,—NR′C(O)N(R′)—, —N(R′)SO₂N(R′)—, —OC(O)—, or —C(O)N(R′)—O—; eachoccurrence of T₁ is independently C₁₋₆ alkylene chain optionallysubstituted with R^(3a), wherein the alkylene chain optionally isinterrupted by —C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O)₂—,—C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—,—N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)SO₂N(R′)—, —OC(O)—, or—C(O)N(R′)—O— or wherein T¹ or a portion thereof optionally forms partof an optionally substituted 3-7 membered cycloaliphatic or heterocyclylring;
 23. The compound of claim 21, wherein the phenyl group issubstituted with 1 or 2 occurrences of R^(4a), wherein each occurrenceof R^(4a) is independently halogen, —CN, —C(O)N(R^(4c))₂, —O(R^(4c)),—S(R^(4d)), —N(R^(4c))₂, —C(O)O-T₁-R^(4e), -R^(4d), or wherein twooccurrences of R^(4b), taken together with their intervening atoms, forma 5-6-membered spiro or fused carbocyclic or heterocyclyl ring.
 24. Thecompound of claim 4 or 5, wherein R³ is —OR^(3b), —SR^(3c),—V₁-T₁-R^(3d), or T₁-R^(3d), wherein V₁ is O or S, and T₁ is —CH₂— or—CH₂—CH₂—.
 25. The compound of claim 24, wherein R^(3b), R^(3c), andR^(3d) are each independently an optionally substituted group selectedfrom C₁₋₄alkenyl, C₁₋₄alkynyl, C₁₋₄alkyl, 5-10-membered heterocyclylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur. 26.The compound of claim 25, wherein R^(3b), R^(3c), and R^(3d) are eachindependently optionally substituted C₁₋₄alkenyl, C₁₋₄alkynyl,C₁₋₄alkyl, or an optionally substituted group selected from:


27. The compound of claim 24, wherein R^(3b), R^(3c), and R^(3d) areeach independently an optionally substituted ring selected from bicyclic8-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur or 8-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur. 28.The compound of claim 27, wherein R^(3b), R^(3c), and R^(3d) are eachindependently optionally substituted with 1-3 occurrences of R^(3e),wherein R^(3e) is R^(f), halogen, —N(R^(g))₂, —OR^(g), —SR^(f),—S(O)₂R^(f), —COR^(f), —COOR^(g), —CON(R^(g))₂, —CON(R^(g))₂,—S(O)₂N(R^(g))₂, —CC(O)N(R^(g))₂, —NR′C(O)R^(f), —NR′S(O)₂R^(f), whereinR^(f) is an optionally substituted C₁₋₆ aliphatic group and R^(g) ishydrogen or an optionally substituted C₁₋₆ aliphatic group.
 29. Thecompound of claim 28, wherein R^(3b), R^(3c), and R^(3d) are eachindependently optionally substituted with 1-3 occurrences of R^(3e),wherein R^(3e) is C₁₋₄aliphatic, C₁₋₄haloaliphatic, or halogen.
 30. Thecompound of claim 5, wherein r is 2 and two occurrences of R³, takentogether, form an optionally substituted 3-6-membered spiro carbocyclicor heterocyclic ring selected from:


31. The compound of claim 4, wherein the compound has the structure offormula I-C:


32. The compound of claim 31, wherein X is O and the compound has thestructure of formula I-D:

wherein: a) R¹ is an optionally substituted 5-8-membered monocyclic or7-10-membered bicyclic heterocyclyl or heteroaryl ring having 1-4heteroatoms independently selected from N, O, or S, wherein R¹ isoptionally substituted with 1-3 occurrences of R^(1a), wherein eachoccurrence of R^(1a) is independently halogen, ═O, ═S, —CN, —N₂,-R^(1c), —N(R^(1b))₂, —OR^(1b), —SR^(1c), —S(O)₂R^(1c), —C(O)R^(1b),C(O)OR^(1b), C(O)N(R^(1b))₂, —S(O)₂N(R^(1b))₂, —OC(O)N(R^(1b))₂,—N(R′)C(O)R^(1b), —N(R′)SO₂R^(1c), —N(R′)C(O)OR^(1b),—N(R′)C(O)N(R^(1b))₂, or —N(R′)SO₂N(R^(1b))₂, or two occurences ofR^(1b) or R^(1c) are optionally taken together with their interveningatom(s) to form an optionally substituted spiro, fused, or bridged ringselected from 6-membered aryl, 3-6-membered cycloaliphatic, 3-7-memberedheterocyclyl having 1-3 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3heteroatoms independently selected from nitrogen, oxygen, or sulfur ortwo occurrences of R^(1b), taken together with the nitrogen atom towhich they are bound, form an optionally substituted 3-7-memberedheterocyclyl ring having 1-3 additional heteroatoms selected fromnitrogen, oxygen, or sulfur, wherein: each occurrence of R^(1b) isindependently hydrogen or an optionally substituted group selected fromC₁₋₆aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur; andeach occurrence of R^(1c) is independently an optionally substitutedgroup selected from C₁₋₆aliphatic, 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; b) Y is —NH(CO)CH₂—, —NHS(O)₂CH₂, —NHC(O)—,—NH(CO)CH₂NH—, or —NHS(O)₂—; c) m is 0 or 1, and when m is 1 R² is anoptionally substituted group selected from a monocyclic 3-7-memberedheterocyclyl having 1-2 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, a bicyclic 7-10-membered heterocyclylhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, orsulfur, a monocyclic 5-6-membered heteroaryl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or a7-10-membered heteroaryl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur; and d) R³ is —OR^(3b), —SR^(3c),—V₁-T₁-R^(3d), or T₁-R^(3d), wherein V₁ is O or S, and T₁ is —CH₂— or—CH₂—CH₂—, wherein R^(3b), R^(3c), and R^(3d) are each independently anoptionally substituted group selected from C₁₋₄alkenyl, C₁₋₄alkynyl,C₁₋₄alkyl, 5-10-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur.
 33. The compound of claim 32,wherein: a) R¹ is an optionally substituted group selected from:

 and each occurrence of R^(1a) is independently ═O, halogen, —R^(1c),—N(R^(1b))₂, —OR^(1b), or —SR^(1c); and b) R^(3b), R^(3c), and R^(3d)are each independently optionally substituted C₁₋₄alkenyl, C₁₋₄alkynyl,C₁₋₄alkyl, or an optionally substituted group selected from:

 wherein R^(3b), R^(3c), and R^(3d) are each independently optionallysubstituted with 1-3 occurrences of R^(3e), wherein R^(3e) isC₁₋₄aliphatic, C₁₋₄haloaliphatic, or halogen.
 34. The compound of claim31, wherein X is N(W—R⁴), and the compound has the structure of formulaI-E:

wherein: a) R¹ is an optionally substituted 5-8-membered monocyclic or7-10-membered bicyclic heterocyclyl or heteroaryl ring having 1-4heteroatoms independently selected from N, O, or S, wherein R¹ isoptionally substituted with 1-3 occurrences of R^(1a), wherein eachoccurrence of R^(1a) is independently halogen, ═O, —CN, —NO₂, R^(1c),—N(R^(1b))₂, —OR^(1b), —SR^(1c), S(O)₂R^(1c), —C(O)R^(1b), —C(O)OR^(1b),—C(O)N(R^(1b))₂, —S(O)₂N(R^(1b))₂, —OC(O)N(R^(1b))₂, —N(R′)C(O)R^(1b),—N(R′)SO₂R^(1c), —N(R′)C(O)OR^(1b), —N(R′)C(O)N(R^(1b))₂, or—N(R′)SO₂N(R^(1b))₂, or two occurences of R^(1b) or R^(1c) areoptionally taken together with their intervening atom(s) to form anoptionally substituted spiro, fused, or bridged ring selected from6-membered aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclylhaving 1-3 heteroatoms independently selected from nitrogen, oxygen, orsulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur or two occurrences of R^(1b),taken together with the nitrogen atom to which they are bound, form anoptionally substituted 3-7-membered heterocyclyl ring having 1-3additional heteroatoms selected from nitrogen, oxygen, or sulfur,wherein: each occurrence of R^(1b) is independently hydrogen or anoptionally substituted group selected from C₁₋₆aliphatic, 3-10-memberedcycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur; and each occurrence of R^(1c)is independently an optionally substituted group selected fromC₁₋₆aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur; b)Y is —NH(CO)CH₂—, —NHS(O)₂CH₂, —NHC(O)—, —NH(CO)CH₂NH—, or —NHS(O)₂—; c)m is 0; d) R³ is OR^(3b), —SR^(3c), —V₁-T₁-R^(3d), or T₁-R^(3d), whereinV₁ is O or S, and T₁ is —CH₂— or —CH₂—CH₂—, wherein R^(3b), R^(3c), andR^(3d) are each independently an optionally substituted group selectedfrom C₁₋₄alkenyl, C₁₋₄alkynyl, C₁₋₄alkyl, 5-10-membered heterocyclylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur; e)W is absent, and f) R⁴ is an optionally substituted group selected froma monocyclic 3-7-membered heterocyclyl having 1-2 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, a bicyclic7-10-membered heterocyclyl having 1-2 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, a monocyclic 5-6-membered heteroarylhaving 1-3 heteroatoms independently selected from nitrogen, oxygen, orsulfur, or a 7-10-membered heteroaryl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.
 35. Thecompound of claim 31, wherein X is N(W—R⁴), and the compound has thestructure of formula I-E:

wherein: a) R¹ is an optionally substituted 5-8-membered monocyclic or7-10-membered bicyclic heterocyclyl or heteroaryl ring having 1-4heteroatoms independently selected from N, O, or S, wherein R¹ isoptionally substituted with 1-3 occurrences of R^(1a), wherein eachoccurrence of R^(1a) is independently halogen, ═O, —CN, —NO₂, -R^(1c),—N(R^(1b))₂, —OR^(1b), —SR^(1c), —S(O)₂R^(1c), —C(O)R^(1b), C(O)OR^(1b),C(O)N(R^(1b))₂, —S(O)₂N(R^(1b))₂, —OC(O)N(R^(1b))₂, —N(R′)C(O)R^(1b),—N(R′)SO₂R^(1c), —N(R′)C(O)OR^(1b), —N(R′)C(O)N(R^(1b))₂, or—N(R′)SO₂N(R^(1b))₂, or two occurences of R^(1b) or R^(1c) areoptionally taken together with their intervening atom(s) to form anoptionally substituted spiro, fused, or bridged ring selected from6-membered aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclylhaving 1-3 heteroatoms independently selected from nitrogen, oxygen, orsulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur or two occurrences of R^(1b),taken together with the nitrogen atom to which they are bound, form anoptionally substituted 3-7-membered heterocyclyl ring having 1-3additional heteroatoms selected from nitrogen, oxygen, or sulfur,wherein: each occurrence of R^(1b) is independently hydrogen or anoptionally substituted group selected from C₁₋₆aliphatic, 3-10-memberedcycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur; and each occurrence of R^(1c)is independently an optionally substituted group selected fromC₁₋₆aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur; b)Y is —NH(CO)CH₂—, —NHS(O)₂CH₂, —NHC(O)—, —NH(CO)CH₂NH—, or —NHS(O)₂—; c)m is 0; d) R³ is —OR^(3b), —SR^(3c), —V₁-T₁-R^(3d), or T₁-R^(3d),wherein V₁ is O or S, and T₁ is —CH₂— or —CH₂—CH₂—, wherein R^(3b),R^(3c), and R^(3d) are each independently an optionally substitutedgroup selected from C₁₋₄alkenyl, C₁₋₄alkynyl, C₁₋₄alkyl, 5-10-memberedheterocyclyl having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; e) W is absent, and f) R⁴ is optionally substitutedphenyl.
 36. The compound of claim 34 or 35, wherein R⁴ is optionallysubstituted with 1-3 occurrences of R^(4a) each occurrence of R^(4a) isindependently -R^(4b), -T₁-R^(4e), or —V₁-T₁-R^(4e), wherein: eachoccurrence of -R^(4b) is independently halogen, —CN, —NO₂, -R^(4d),—N(R^(4c))₂, —OR^(4c), —SR^(4d), —S(O)₂R^(4d), —C(O)R^(4c),—C(O)OR^(4c), —C(O)N(R^(4c))₂, —S(O)₂N(R^(4c))₂, —OC(O)N(R^(4c))₂,—N(R′)C(O)R^(4c), —N(R′)SO₂R^(4d), —N(R′)C(O)OR^(4c),—N(R′)C(O)N(R^(4c))₂, or —N(R′)SO₂N(R^(4c))₂, or two occurences ofR^(4b), R^(4c) or R^(4d) are optionally taken together with theirintervening atom(s) to form an optionally substituted spiro, fused, orbridged ring selected from 6-membered aryl, 3-6-membered cycloaliphatic,3-7-membered heterocyclyl having 1-3 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3heteroatoms independently selected from nitrogen, oxygen, or sulfur, ortwo occurrences of R^(4c), taken together with the nitrogen atom towhich they are bound, form an optionally substituted 3-7-memberedheterocyclyl ring having 1-3 additional heteroatoms selected fromnitrogen, oxygen, or sulfur; each occurrence of R^(4c) is independentlyhydrogen or an optionally substituted group selected from C₁₋₆aliphatic,3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur,6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; each occurrenceof R^(4d) is independently an optionally substituted group selected fromC₁₋₆aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur;each occurrence of R^(4e) is independently an optionally substitutedgroup selected from 3-10-membered cycloaliphatic, 3-10-memberedheterocyclyl having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; each occurrence of V₁ is independently —C(R′)═C(R′)—,—C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R′)—,—S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO₂—, —N(R′)C(O)O—,—NR′C(O)N(R′)—, —N(R′)SO₂N(R′)—, —OC(O)—, or —C(O)N(R′)—O—; and eachoccurrence of T₁ is independently C₁₋₆ alkylene chain optionallysubstituted with R^(3a), wherein the alkylene chain optionally isinterrupted by —C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O)₂—,—C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—,—N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)SO₂N(R′)—, —OC(O)—, or—C(O)N(R′)—O— or wherein T¹ or a portion thereof optionally forms partof an optionally substituted 3-7 membered cycloaliphatic or heterocyclylring.
 37. The compound of claim 34 or 35, wherein: a) R¹ is anoptionally substituted group selected from:

 and each occurrence of R^(1a) is independently ═O, halogen, R^(1c),—N(R^(1b))₂, —OR^(1b), or —SR^(1c); and b) R^(3b), R^(3c), and R^(3d)are each independently optionally substituted C₁₋₄alkenyl, C₁₋₄alkynyl,C₁₋₄alkyl, or an optionally substituted group selected from:

 wherein R^(3b), R^(3c), and R^(3d) are each independently optionallysubstituted with 1-3 occurrences of R^(3e), wherein R^(3e) isC₁₋₄aliphatic, C₁₋₄haloaliphatic, or halogen.
 38. The compound of claim5, having the structure of formula I-F:

or a pharmaceutically acceptable salt thereof, wherein the twooccurrences of R³, taken together, form an optionally substituted3-6-membered spiro carbocyclic or heterocyclic ring.
 39. The compound ofclaim 38, wherein X is O and the compound has the structure of formulaI-G:

or a pharmaceutically acceptable salt thereof, wherein: a) R¹ is anoptionally substituted 5-8-membered monocyclic or 7-10-membered bicyclicheterocyclyl or heteroaryl ring having 1-4 heteroatoms independentlyselected from N, O, or S, wherein R¹ is optionally substituted with 1-3occurrences of R^(1a), wherein each occurrence of R^(1a) isindependently halogen, ═O, ═S, —CN, —NO₂, -R^(1c), —N(R^(1b))₂,—OR^(1b), —SR^(1c), —S(O)₂R^(1c), —C(O)R^(1b), C(O)OR^(1b),C(O)N(R^(1b))₂, —S(O)₂N(R^(1b))₂, —OC(O)N(R^(1b))₂, —N(R′)C(O)R^(1b),—N(R′)SO₂R^(1c), —N(R′)C(O)OR^(1b), —N(R′)C(O)N(R^(1b))₂, or—N(R′)SO₂N(R^(1b))₂, or two occurences of R^(1b) or R^(1c) areoptionally taken together with their intervening atom(s) to form anoptionally substituted spiro, fused, or bridged ring selected from6-membered aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclylhaving 1-3 heteroatoms independently selected from nitrogen, oxygen, orsulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur or two occurrences of R^(1b),taken together with the nitrogen atom to which they are bound, form anoptionally substituted 3-7-membered heterocyclyl ring having 1-3additional heteroatoms selected from nitrogen, oxygen, or sulfur,wherein: each occurrence of R^(1b) is independently hydrogen or anoptionally substituted group selected from C₁₋₆aliphatic, 3-10-memberedcycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur; and each occurrence of R^(1c)is independently an optionally substituted group selected fromC₁₋₆aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur; b)Y is —NH(CO)CH₂—, —NHS(O)₂CH₂, —NHC(O)—, —NH(CO)CH₂NH—, or —NHS(O)₂—; c)m is 0 or 1, and when m is 1 R² is an optionally substituted groupselected from a monocyclic 3-7-membered heterocyclyl having 1-2heteroatoms independently selected from nitrogen, oxygen, or sulfur, abicyclic 7-10-membered heterocyclyl having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, a monocyclic 5-6-memberedheteroaryl having 1-3 heteroatoms independently selected from nitrogen,oxygen, or sulfur, or a 7-10-membered heteroaryl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; and d) whereinthe two occurrences of R³, taken together, form an optionallysubstituted 3-6-membered spiro carbocyclic or heterocyclic ring.
 40. Thecompound of claim 39, wherein: a) R¹ is an optionally substituted groupselected from:

 and each occurrence of R^(1a) is independently ═O, halogen, R^(1c),—N(R^(1b))₂, —OR^(1b), or SR^(1c); and b) the spiro ring formed from thetwo occurrences of R³ is an optionally substituted ring selected from:


41. The compound of claim 38, wherein X is N(W—R⁴), and the compound hasthe structure of formula I-H:

or a pharmaceutically acceptable salt thereof, wherein: a) R¹ is anoptionally substituted 5-8-membered monocyclic or 7-10-membered bicyclicheterocyclyl or heteroaryl ring having 1-4 heteroatoms independentlyselected from N, O, or S, wherein R¹ is optionally substituted with 1-3occurrences of R^(1a), wherein each occurrence of R^(1a) isindependently halogen, ═O, —CN, —NO₂, -R^(1c), —N(R^(1b))₂, —OR^(1b),—SR^(1c), S(O)₂R^(1c), —C(O)R^(1b), C(O)OR^(1b), —C(O)N(R^(1b))₂,—S(O)₂N(R^(1b))₂, —OC(O)N(R^(1b))₂, —N(R′)C(O)R^(1b), —N(R′)SO₂R^(1c),—N(R′)C(O)OR^(1b), —N(R′)C(O)N(R^(1b))₂, or —N(R′)SO₂N(R^(1b))₂, or twooccurences of R^(1b) or R^(1c) are optionally taken together with theirintervening atom(s) to form an optionally substituted spiro, fused, orbridged ring selected from 6-membered aryl, 3-6-membered cycloaliphatic,3-7-membered heterocyclyl having 1-3 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3heteroatoms independently selected from nitrogen, oxygen, or sulfur ortwo occurrences of R^(1b), taken together with the nitrogen atom towhich they are bound, form an optionally substituted 3-7-memberedheterocyclyl ring having 1-3 additional heteroatoms selected fromnitrogen, oxygen, or sulfur, wherein: each occurrence of R^(1b) isindependently hydrogen or an optionally substituted group selected fromC₁₋₆aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur; andeach occurrence of R^(1c) is independently an optionally substitutedgroup selected from C₁₋₆aliphatic, 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; b) Y is —NH(CO)CH₂—, —NHS(O)₂CH₂, —NHC(O)—,—NH(CO)CH₂NH—, or —NHS(O)₂—; c) m is 0; d) wherein the two occurrencesof R³, taken together, form an optionally substituted 3-6-membered spirocarbocyclic or heterocyclic ring; e) W is absent, and f) R⁴ is anoptionally substituted group selected from a monocyclic 3-7-memberedheterocyclyl having 1-2 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, a bicyclic 7-10-membered heterocyclylhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, orsulfur, a monocyclic 5-6-membered heteroaryl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or a7-10-membered heteroaryl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.
 42. The compound of claim 38, whereinX is N(W—R⁴), and the compound has the structure of formula I-H:

or a pharmaceutically acceptable salt thereof, wherein: a) R¹ is anoptionally substituted 5-8-membered monocyclic or 7-10-membered bicyclicheterocyclyl or heteroaryl ring having 1-4 heteroatoms independentlyselected from N, O, or S, wherein R¹ is optionally substituted with 1-3occurrences of R^(1a), wherein each occurrence of R^(1a) isindependently halogen, ═O, —CN, —NO₂, -R^(1c), —N(R^(1b))₂, —OR^(1b),—SR^(1c), —S(O)₂R^(1c), C(O)R^(1b), C(O)OR^(1b), —C(O)N(R^(1b))₂,—S(O)₂N(R^(1b))₂, —OC(O)N(R^(1b))₂, —N(R′)C(O)R^(1b), —N(R′)SO₂R^(1c),—N(R′)C(O)OR^(1b), N(R′)C(O)N(R^(1b))₂, or —N(R′)SO₂N(R^(1b))₂, or twooccurences of R^(1b) or R^(1c) are optionally taken together with theirintervening atom(s) to form an optionally substituted spiro, fused, orbridged ring selected from 6-membered aryl, 3-6-membered cycloaliphatic,3-7-membered heterocyclyl having 1-3 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3heteroatoms independently selected from nitrogen, oxygen, or sulfur ortwo occurrences of R^(1b), taken together with the nitrogen atom towhich they are bound, form an optionally substituted 3-7-memberedheterocyclyl ring having 1-3 additional heteroatoms selected fromnitrogen, oxygen, or sulfur, wherein: each occurrence of R^(1b) isindependently hydrogen or an optionally substituted group selected fromC₁₋₆aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur; andeach occurrence of R^(1c) is independently an optionally substitutedgroup selected from C₁₋₆aliphatic, 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; b) Y is —NH(CO)CH₂—, —NHS(O)₂CH₂, —NHC(O)—,—NH(CO)CH₂NH—, or —NHS(O)₂—; c) m is 0; d) the spiro ring formed fromthe two occurrences of R³ is an optionally substituted ring selectedfrom:

e) W is absent, and f) R⁴ is optionally substituted phenyl.
 43. Thecompound of claim 41 or 42, wherein R⁴ is optionally substituted with1-3 occurrences of R^(4a) and each occurrence of R^(4a) is independently-R^(4b), -T₁-R^(4e), or —V₁-T₁-R^(4e), wherein: each occurrence of-R^(4b) is independently halogen, —CN, —NO₂, R^(4d), —N(R^(4c))₂,—OR^(4c), —SR^(4d), —S(O)₂R^(4d), —C(O)R^(4c), —C(O)OR^(4c),—C(O)N(R^(4c))₂, —S(O)₂N(R^(4c))₂, —OC(O)N(R^(4c))₂, —N(R′)C(O)R^(4c),—N(R′)SO₂R^(4d), —N(R′)C(O)OR^(e), —N(R′)C(O)N(R^(4c))₂, or—N(R′)SO₂N(R^(4c))₂, or two occurences of R^(4b), R^(4c) or R^(4d) areoptionally taken together with their intervening atom(s) to form anoptionally substituted spiro, fused, or bridged ring selected from6-membered aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclylhaving 1-3 heteroatoms independently selected from nitrogen, oxygen, orsulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or two occurrences of R^(4c),taken together with the nitrogen atom to which they are bound, form anoptionally substituted 3-7-membered heterocyclyl ring having 1-3additional heteroatoms selected from nitrogen, oxygen, or sulfur; eachoccurrence of R^(4c) is independently hydrogen or an optionallysubstituted group selected from C₁₋₆aliphatic, 3-10-memberedcycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur; each occurrence of R^(4d) isindependently an optionally substituted group selected fromC₁₋₆aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur;each occurrence of R^(4e) is independently an optionally substitutedgroup selected from 3-10-membered cycloaliphatic, 3-10-memberedheterocyclyl having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; each occurrence of V₁ is independently —C(R′)═C(R′)—,—C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R′)—,—S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO₂—, —N(R′)C(O)O—,—NR′C(O)N(R′)—, —N(R′)SO₂N(R′)—, —OC(O)—, or —C(O)N(R′)—O—; and eachoccurrence of T₁ is independently C₁₋₆ alkylene chain optionallysubstituted with R^(3a), wherein the alkylene chain optionally isinterrupted by —C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O)₂—,—C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—,—N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)SO₂N(R′)—, —OC(O)—, or—C(O)N(R′)—O— or wherein T¹ or a portion thereof optionally forms partof an optionally substituted 3-7 membered cycloaliphatic or heterocyclylring.
 44. The compound of claim 41 or 42, wherein: a) R¹ is anoptionally substituted group selected from:

 and each occurrence of R^(1a) is independently ═O, halogen, -R^(1c),—N(R^(1b))₂, —OR^(1b), or —SR^(1c); and b) the Spiro ring formed fromthe two occurrences of R³ is an optionally substituted ring selectedfrom:


45. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier or diluent and a compound of formula I

or a pharmaceutically acceptable salt thereof, wherein: Y is -Y₁-Y₂-,wherein: Y₁ is —SO₂N(R′)—, —C(O)N(R′)—; —C(O)N(R′)C(O)—, —N(R′)SO₂—,—N(R′)SO₂N(R′)—, —N(R′)C(O)—, —NR′C(O)N(R′)—, or —N(R′)C(O)O—; and Y₂ isabsent or is an optionally substituted C₁₋₆ alkylene chain, wherein oneor two methylene units of Y₂ are optionally and independentlyinterrupted by —O—, —S—, —N(R′)—, —C(O)—, —OC(O)—, —C(O)O—, —S(O)—,—S(O)₂—, —C(O)N(R′)—, —N(R′)C(O)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—,—OC(O)N(R′)—, —N(R′)S(O)₂—, or —S(O)₂N(R′)—, or wherein Y₂, or a portionthereof, is an optionally substituted ring selected from 3-6-memberedcycloaliphatic, 3-6-membered heterocyclyl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-memberedaryl, or 5-6-membered heteroaryl having 1-3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur; each R′ is independentlyhydrogen or optionally substituted C₁₋₆aliphatic; R¹ is an optionallysubstituted group selected from 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; ring A is substituted at one or more carbon atomswith m independent occurrences of R²; m is 0-6; each occurrence of R² isindependently halogen, ═O, ═S, —CN, -R^(2b), —N(R^(2a))₂, —OR^(2a),SR^(2b), S(O)₂R^(2b), —C(O)R^(2a), —C(O)OR^(2a), —C(O)N(R^(2a))₂,—S(O)₂N(R^(2a))₂, —OC(O)N(R^(2a))₂, —N(R′)C(O)R^(2a), —N(R′)SO₂R^(2b),—N(R′)C(O)OR^(2a), —N(R′)C(O)N(R^(2a))₂, or —N(R′)SO₂N(R^(2a))₂, or twooccurences of R^(2a) or R^(2b) are optionally taken together with theirintervening atom(s) to form an optionally substituted spiro, fused, orbridged ring selected from 6-membered aryl, 3-6-membered cycloaliphatic,3-7-membered heterocyclyl having 1-3 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3heteroatoms independently selected from nitrogen, oxygen, or sulfur, ortwo occurrences of R^(2a), taken together with the nitrogen atom towhich they are bound, form an optionally substituted 3-7-memberedheterocyclyl ring having 1-3 additional heteroatoms selected fromnitrogen, oxygen, or sulfur; each occurrence of R^(2a) is independentlyhydrogen or an optionally substituted group selected from C₁₋₆aliphatic,3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur,6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; each occurrenceof R^(2b) is independently an optionally substituted group selected fromC₁₋₆aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur;ring B is substituted with r independent occurrences of -R³; r is 0-6;each occurrence of R³ is independently -R^(3a), -T₁-R^(3d), or—V₁-T₁-R^(3d), wherein: each occurrence of R^(3a) is independentlyhalogen, —CN, —NO₂, R^(3c), N(R^(3b))₂, —OR^(3b), —SR^(3c),—S(O)₂R^(3c), —C(O)R^(3b), —C(O)OR^(3b), C(O)N(R^(3b))₂,S(O)₂N(R^(3b))₂, —OC(O)N(R^(3b))₂, —N(R′)C(O)R^(3b), N(R′)SO₂R^(3c),—N(R′)C(O)OR^(3b), —N(R′)C(O)N(R^(3b))₂, or —N(R′)SO₂N(R^(3b))₂, or twooccurences of R^(3b) or R^(3c) are optionally taken together with theirintervening atom(s) to form an optionally substituted spiro, fused, orbridged ring selected from 6-membered aryl, 3-6-membered cycloaliphatic,3-7-membered heterocyclyl having 1-3 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3heteroatoms independently selected from nitrogen, oxygen, or sulfur, ortwo occurrences of R^(3b), taken together with the nitrogen atom towhich they are bound, form an optionally substituted 3-7-memberedheterocyclyl ring having 1-3 additional heteroatoms selected fromnitrogen, oxygen, or sulfur; each occurrence of R^(3b) is independentlyhydrogen or an optionally substituted group selected from C₁₋₆aliphatic,3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur,6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; each occurrenceof R^(3c) is independently an optionally substituted group selected fromC₁₋₆aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur;each occurrence of R^(3d) is independently an optionally substitutedgroup selected from 3-10-membered cycloaliphatic, 3-10-memberedheterocyclyl having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; each occurrence of V₁ is independently —C(R′)═C(R′)—,—C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R′)—,—S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO₂—, —N(R′)C(O)O—,—NR′C(O)N(R′)—, —N(R′)SO₂N(R′)—, —OC(O)—, or —C(O)N(R′)—O—; eachoccurrence of T₁ is independently C₁₋₆ alkylene chain optionallysubstituted with R^(3a), wherein the alkylene chain optionally isinterrupted by —C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O)₂—,—C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—,—N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)SO₂N(R′)—, —OC(O)—, or—C(O)N(R′)—O— or wherein T¹ or a portion thereof optionally forms partof an optionally substituted 3-7 membered cycloaliphatic or heterocyclylring; X is —O—, —S—, —SO₂—, or —N(W—R⁴)—; W is absent or is a groupselected from —W₁-L₂-W₂-, wherein W₁ and W₂ are each independentlyabsent or are an optionally substituted C₁₋₃alkylene chain, and L₂ isabsent or is a group selected from —N(R)—, —O—, —S—, —S(O)—, —S(O)₂—,—C(O)—, —C(O)O—, —C(O)N(R)—, —S(O)₂N(R)—, —OC(O)N(R)—, —N(R)C(O)—,—N(R)SO₂—, —N(R)C(O)O—, —N(R)C(O)N(R)—, —N(R)SO₂N(R)—, —OC(O)—, or—C(O)N(R)—O—, wherein R is hydrogen or C₁-C₄alkyl, provided that if W₁is absent then L₂ is selected from —C(O)—, —C(O)O—, —C(O)O—, —S(O)—,—S(O)₂—, —C(O)N(R)—, or —S(O)₂N(R)— R⁴ is an optionally substitutedmonocyclic or bicyclic ring selected from 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur, provided that the compound is other than: a)1-Pyrrolidinecarboxamide,3-[6-(4-chlorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl]-N-methyl-N-[(3S)-1-(tetrahydro-2-oxo-3-furanyl)-3-pyrrolidinyl]-,(3S)—; b) Pentitol,1,4-anhydro-2,3,5-trideoxy-3-[(3R)-3-[methyl[[(3S)-3-[methyl[[(4-phenoxyphenyl)amino]carbonyl]amino]-1-pyrrolidinyl]carbonyl]amino]-1-pyrrolidinyl]-;c) 1-Pyrrolidinecarboxamide,N-methyl-3-[methyl[[4′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl]amino]-N-[(3R)-1′-(phenylmethyl)[1,3′-bipyrrolidin]-3-yl]-, (3S)—; d) Pentitol,1,4-anhydro-2,3,5-trideoxy-3-[(3R)-3-[methyl[[(3S)-3-[methyl[[4′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl]amino]-1-pyrrolidinyl]carbonyl]amino]-1-pyrrolidinyl]-;e) [1,3′-Bipyrrolidine]-1′-carboxylic acid,3-[(hydroxyamino)carbonyl]-4-[[4-[(2-methyl-4-quinolinyl)methoxy]benzoyl]amino]-,1,1-dimethylethyl ester, (3R,4R)-rel-; and f)[1,3′-Bipyrrolidine]-3-carboxamide,N-hydroxy-4-[[4-[(2-methyl-4-quinolinyl)methoxy]benzoyl]amino]-,(3R,4R)-rel-.
 46. A method for treating an inflammatory disordercomprising administering to a subject an effective amount of a compoundof formula I

or a pharmaceutically acceptable salt thereof, wherein: Y is -Y₁-Y₂-,wherein: Y₁ is —SO₂N(R′)—, —C(O)N(R′)—; —C(O)N(R′)C(O)—, —N(R′)SO₂—,—N(R′)SO₂N(R′)—, —N(R′)C(O)—, —NR′C(O)N(R′)—, or —N(R′)C(O)O—; and Y₂ isabsent or is an optionally substituted C₁₋₆ alkylene chain, wherein oneor two methylene units of Y₂ are optionally and independentlyinterrupted by —O—, —S—, —N(R′)—, —C(O)—, —OC(O)—, —C(O)O—, —S(O)—,—S(O)₂—, —C(O)N(R′)—, —N(R′)C(O)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—,—OC(O)N(R′)—, —N(R′)S(O)₂—, or —S(O)₂N(R′)—, or wherein Y₂, or a portionthereof, is an optionally substituted ring selected from 3-6-memberedcycloaliphatic, 3-6-membered heterocyclyl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-memberedaryl, or 5-6-membered heteroaryl having 1-3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur; each R′ is independentlyhydrogen or optionally substituted C₁₋₆aliphatic; R¹ is an optionallysubstituted group selected from 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; ring A is substituted at one or more carbon atomswith m independent occurrences of R²; m is 0-6; each occurrence of R² isindependently halogen, ═O, ═S, —CN, -R^(2b), —N(R^(2a))₂, —OR^(2a),—SR^(2b), —S(O)₂R^(2b), —C(O)R^(2a), —C(O)OR^(2a), —C(O)N(R^(2a))₂,—S(O)₂N(R^(2a))₂, —OC(O)N(R^(2a))₂, —N(R′)C(O)R^(2a), —N(R′)SO₂R^(2b),—N(R′)C(O)OR^(2a), —N(R′)C(O)N(R^(2a))₂, or —N(R′)SO₂N(R^(2a))₂, or twooccurences of R^(2a) or R^(2b) are optionally taken together with theirintervening atom(s) to form an optionally substituted spiro, fused, orbridged ring selected from 6-membered aryl, 3-6-membered cycloaliphatic,3-7-membered heterocyclyl having 1-3 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3heteroatoms independently selected from nitrogen, oxygen, or sulfur, ortwo occurrences of R², taken together with the nitrogen atom to whichthey are bound, form an optionally substituted 3-7-membered heterocyclylring having 1-3 additional heteroatoms selected from nitrogen, oxygen,or sulfur; each occurrence of R^(2a) is independently hydrogen or anoptionally substituted group selected from C₁₋₆aliphatic, 3-10-memberedcycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur; each occurrence of R^(2b) isindependently an optionally substituted group selected fromC₁₋₆aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur;ring B is substituted with r independent occurrences of -R³; r is 0-6;each occurrence of R³ is independently -R^(3a), -T₁-R^(3d), or—V₁-T₁-R^(3d), wherein: each occurrence of -R^(3a) is independentlyhalogen, —CN, —NO₂, -R^(3c), —N(R^(3b))₂, —OR^(3b), —SR^(3c),—S(O)₂R^(3c), —C(O)R^(3b), —C(O)OR^(3b), —C(O)N(R^(3b))₂,—S(O)₂N(R^(3b))₂, —OC(O)N(R^(3b))₂, —N(R′)C(O)R^(3b), —N(R′)SO₂R^(3c),—N(R′)C(O)OR^(3b), —N(R′)C(O)N(R^(3b))₂, or —N(R′)SO₂N(R^(3b))₂, or twooccurences of R^(3b) or R^(3c) are optionally taken together with theirintervening atom(s) to form an optionally substituted spiro, fused, orbridged ring selected from 6-membered aryl, 3-6-membered cycloaliphatic,3-7-membered heterocyclyl having 1-3 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3heteroatoms independently selected from nitrogen, oxygen, or sulfur, ortwo occurrences of R^(3b), taken together with the nitrogen atom towhich they are bound, form an optionally substituted 3-7-memberedheterocyclyl ring having 1-3 additional heteroatoms selected fromnitrogen, oxygen, or sulfur; each occurrence of R^(3b) is independentlyhydrogen or an optionally substituted group selected from C₁₋₆aliphatic,3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur,6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; each occurrenceof R^(3c) is independently an optionally substituted group selected fromC₁₋₆aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur;each occurrence of R^(3d) is independently an optionally substitutedgroup selected from 3-10-membered cycloaliphatic, 3-10-memberedheterocyclyl having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; each occurrence of V₁ is independently —C(R′)═C(R′)—,—C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R′)—,—S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO₂—, —N(R′)C(O)O—,—NR′C(O)N(R′)—, —N(R′)SO₂N(R′)—, —OC(O)—, or —C(O)N(R′)—O—; eachoccurrence of T₁ is independently C₁₋₆ alkylene chain optionallysubstituted with R³, wherein the alkylene chain optionally isinterrupted by —C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O)₂—,—C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O)₂N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—,—N(R′)SO₂—, —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)SO₂N(R′)—, —OC(O)—, or—C(O)N(R′)—O— or wherein T¹ or a portion thereof optionally forms partof an optionally substituted 3-7 membered cycloaliphatic or heterocyclylring; X is —O—, —S—, —SO₂—, or —N(W—R⁴)—; W is absent or is a groupselected from —W₁-L₂-W₂-, wherein W₁ and W₂ are each independentlyabsent or are an optionally substituted C₁₋₃alkylene chain, and L₂ isabsent or is a group selected from —N(R)—, —O—, —S—, —S(O)—, —S(O)₂—,—C(O)—, —C(O)O—, —C(O)N(R)—, —S(O)₂N(R)—, —OC(O)N(R)—, —N(R)C(O)—,—N(R)SO₂—, —N(R)C(O)O—, —N(R)C(O)N(R)—, —N(R)SO₂N(R)—, —OC(O)—, or—C(O)N(R)—O—, wherein R is hydrogen or C₁-C₄alkyl, provided that if W₁is absent then L₂ is selected from —C(O)—, —C(O)O—, —C(O)O—, —S(O)—,—S(O)₂—, —C(O)N(R)—, or —S(O)₂N(R)— R⁴ is an optionally substitutedmonocyclic or bicyclic ring selected from 3-10-membered cycloaliphatic,3-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur, provided that the compound is other than: a)[1,3′-Bipyrrolidine]-1′-carboxylic acid,3-[(hydroxyamino)carbonyl]-4-[[4-[(2-methyl-4-quinolinyl)methoxy]benzoyl]amino]-,1,1-dimethylethyl ester, (3R,4R)-rel-; and b)[1,3′-Bipyrrolidine]-3-carboxamide,N-hydroxy-4-[[4-[(2-methyl-4-quinolinyl)methoxy]benzoyl]amino]-,(3R,4R)-rel-.
 47. The method of claim 46, wherein the disorder isrheumatoid arthritis, multiple sclerosis, scleroderma, atherosclerosis,neuropathic pain, and type II diabetes.
 48. The method of claim 47,wherein the disorder is rheumatoid arthritis or multiple sclerosis.